ID ADT1_HUMAN Reviewed; 298 AA. AC P12235; D3DP59; DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 4. DT 28-JAN-2026, entry version 253. DE RecName: Full=ADP/ATP translocase 1 {ECO:0000305}; DE AltName: Full=ADP,ATP carrier protein 1 {ECO:0000250|UniProtKB:P48962}; DE AltName: Full=ADP,ATP carrier protein, heart/skeletal muscle isoform T1 {ECO:0000303|PubMed:2541251}; DE AltName: Full=Adenine nucleotide translocator 1 {ECO:0000303|PubMed:2823266}; DE Short=ANT 1 {ECO:0000303|PubMed:2823266}; DE AltName: Full=Solute carrier family 25 member 4 {ECO:0000305}; GN Name=SLC25A4 {ECO:0000303|PubMed:25732997, ECO:0000312|HGNC:HGNC:10990}; GN Synonyms=AAC1 {ECO:0000250|UniProtKB:P48962}, GN ANT1 {ECO:0000303|PubMed:2823266}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2823266; DOI=10.1073/pnas.84.21.7580; RA Neckelmann N., Li K., Wade R.P., Shuster R., Wallace D.C.; RT "cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a RT leader peptide, divergence from a fibroblast translocator cDNA, and RT coevolution with mitochondrial DNA genes."; RL Proc. Natl. Acad. Sci. U.S.A. 84:7580-7584(1987). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2541251; DOI=10.1016/0022-2836(89)90477-4; RA Cozens A.L., Runswick M.J., Walker J.E.; RT "DNA sequences of two expressed nuclear genes for human mitochondrial RT ADP/ATP translocase."; RL J. Mol. Biol. 206:261-280(1989). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2547778; DOI=10.1016/s0021-9258(18)71632-3; RA Li K., Warner C.K., Hodge J.A., Minoshima S., Kudoh J., Fukuyama R., RA Maekawa M., Shimizu Y., Shimizu N., Wallace D.C.; RT "A human muscle adenine nucleotide translocator gene has four exons, is RT located on chromosome 4, and is differentially expressed."; RL J. Biol. Chem. 264:13998-14004(1989). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=20843780; DOI=10.1093/nar/gkq750; RA Wang W., Shen P., Thiyagarajan S., Lin S., Palm C., Horvath R., RA Klopstock T., Cutler D., Pique L., Schrijver I., Davis R.W., Mindrinos M., RA Speed T.P., Scharfe C.; RT "Identification of rare DNA variants in mitochondrial disorders with RT improved array-based sequencing."; RL Nucleic Acids Res. 39:44-58(2011). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye, Mammary gland, and PNS; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-37. RC TISSUE=Liver; RX PubMed=2829183; DOI=10.1073/pnas.85.2.377; RA Houldsworth J., Attardi G.; RT "Two distinct genes for ADP/ATP translocase are expressed at the mRNA level RT in adult human liver."; RL Proc. Natl. Acad. Sci. U.S.A. 85:377-381(1988). RN [8] RP PROTEIN SEQUENCE OF 2-31; 34-43; 64-92; 141-147; 189-199 AND 273-296, RP CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT GLY-2, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RC TISSUE=B-cell lymphoma; RA Bienvenut W.V.; RL Submitted (OCT-2004) to UniProtKB. RN [9] RP INTERACTION WITH HIV-1 VPR (MICROBIAL INFECTION). RX PubMed=16120388; DOI=10.1016/j.mito.2004.06.012; RA Deniaud A., Brenner C., Kroemer G.; RT "Mitochondrial membrane permeabilization by HIV-1 Vpr."; RL Mitochondrion 4:223-233(2004). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION, RP AND CHARACTERIZATION OF VARIANTS PEOA2 PRO-114 AND MET-289. RX PubMed=21586654; DOI=10.1093/hmg/ddr200; RA Kawamata H., Tiranti V., Magrane J., Chinopoulos C., Manfredi G.; RT "adPEO mutations in ANT1 impair ADP-ATP translocation in muscle RT mitochondria."; RL Hum. Mol. Genet. 20:2964-2974(2011). RN [13] RP INVOLVEMENT IN MTDPS12B. RX PubMed=22187496; DOI=10.1136/jmedgenet-2011-100504; RA Echaniz-Laguna A., Chassagne M., Ceresuela J., Rouvet I., Padet S., RA Acquaviva C., Nataf S., Vinzio S., Bozon D., Mousson de Camaret B.; RT "Complete loss of expression of the ANT1 gene causing cardiomyopathy and RT myopathy."; RL J. Med. Genet. 49:146-150(2012). RN [14] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, AND BIOPHYSICOCHEMICAL RP PROPERTIES. RX PubMed=23173940; DOI=10.3109/09687688.2012.745175; RA Mifsud J., Ravaud S., Krammer E.M., Chipot C., Kunji E.R., RA Pebay-Peyroula E., Dehez F.; RT "The substrate specificity of the human ADP/ATP carrier AAC1."; RL Mol. Membr. Biol. 30:160-168(2013). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [16] RP FUNCTION, INVOLVEMENT IN MTDPS12A, VARIANTS MTDPS12A HIS-80 AND GLY-235, RP CHARACTERIZATION OF VARIANTS MTDPS12A HIS-80 AND GLY-235, CHARACTERIZATION RP OF VARIANTS PEOA2 ASP-90; PRO-98; GLY-104 AND PRO-114, AND CHARACTERIZATION RP OF VARIANTS MTDPS12B ASP-123 AND PRO-236. RX PubMed=27693233; DOI=10.1016/j.ajhg.2016.08.014; RA Thompson K., Majd H., Dallabona C., Reinson K., King M.S., Alston C.L., RA He L., Lodi T., Jones S.A., Fattal-Valevski A., Fraenkel N.D., Saada A., RA Haham A., Isohanni P., Vara R., Barbosa I.A., Simpson M.A., Deshpande C., RA Puusepp S., Bonnen P.E., Rodenburg R.J., Suomalainen A., Ounap K., RA Elpeleg O., Ferrero I., McFarland R., Kunji E.R., Taylor R.W.; RT "Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset RT mitochondrial disease and loss of mitochondrial DNA copy number."; RL Am. J. Hum. Genet. 99:860-876(2016). RN [17] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND IDENTIFICATION BY MASS RP SPECTROMETRY. RX PubMed=27641616; DOI=10.1038/srep33516; RA Marginedas-Freixa I., Hattab C., Bouyer G., Halle F., Chene A., RA Lefevre S.D., Cambot M., Cueff A., Schmitt M., Gamain B., Lacapere J.J., RA Egee S., Bihel F., Le Van Kim C., Ostuni M.A.; RT "TSPO ligands stimulate ZnPPIX transport and ROS accumulation leading to RT the inhibition of P. falciparum growth in human blood."; RL Sci. Rep. 6:33516-33516(2016). RN [18] RP FUNCTION, AND INTERACTION WITH ARHGAP11B. RX PubMed=31883789; DOI=10.1016/j.neuron.2019.11.027; RA Namba T., Doczi J., Pinson A., Xing L., Kalebic N., Wilsch-Braeuninger M., RA Long K.R., Vaid S., Lauer J., Bogdanova A., Borgonovo B., Shevchenko A., RA Keller P., Drechsel D., Kurzchalia T., Wimberger P., Chinopoulos C., RA Huttner W.B.; RT "Human-specific ARHGAP11B acts in mitochondria to expand neocortical RT progenitors by glutaminolysis."; RL Neuron 105:867-881(2020). RN [19] RP FUNCTION. RX PubMed=37278158; DOI=10.15252/embr.202357127; RA Cimadamore-Werthein C., Jaiquel Baron S., King M.S., Springett R., RA Kunji E.R.; RT "Human mitochondrial ADP/ATP carrier SLC25A4 operates with a ping-pong RT kinetic mechanism."; RL EMBO Rep. 24:e57127-e57127(2023). RN [20] RP VARIANTS PEOA2 PRO-114 AND MET-289. RX PubMed=10926541; DOI=10.1126/science.289.5480.782; RA Kaukonen J., Juselius J.K., Tiranti V., Kyttala A., Zeviani M., Comi G.P., RA Keranen J., Peltonen L., Suomalainen A.; RT "Role of adenine nucleotide translocator 1 in mtDNA maintenance."; RL Science 289:782-785(2000). RN [21] RP VARIANT PEOA2 PRO-98. RX PubMed=11756613; DOI=10.1212/wnl.57.12.2295; RA Napoli L., Bordoni A., Zeviani M., Hadjigeorgiou G.M., Sciacco M., RA Tiranti V., Terentiou A., Moggio M., Papadimitriou A., Scarlato G., RA Comi G.P.; RT "A novel missense adenine nucleotide translocator-1 gene mutation in a RT Greek adPEO family."; RL Neurology 57:2295-2298(2001). RN [22] RP VARIANT PEOA2 GLY-104. RX PubMed=12112115; DOI=10.1002/ana.10172; RA Komaki H., Fukazawa T., Houzen H., Yoshida K., Nonaka I., Goto Y.; RT "A novel D104G mutation in the adenine nucleotide translocator 1 gene in RT autosomal dominant progressive external ophthalmoplegia patients with RT mitochondrial DNA with multiple deletions."; RL Ann. Neurol. 51:645-648(2002). RN [23] RP VARIANT PEOA2 MET-289. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [24] RP VARIANT MTDPS12B ASP-123. RX PubMed=16155110; DOI=10.1093/hmg/ddi341; RA Palmieri L., Alberio S., Pisano I., Lodi T., Meznaric-Petrusa M., Zidar J., RA Santoro A., Scarcia P., Fontanesi F., Lamantea E., Ferrero I., Zeviani M.; RT "Complete loss-of-function of the heart/muscle-specific adenine nucleotide RT translocator is associated with mitochondrial myopathy and RT cardiomyopathy."; RL Hum. Mol. Genet. 14:3079-3088(2005). RN [25] RP VARIANT PEOA2 ASP-90. RX PubMed=15792871; DOI=10.1016/j.nmd.2004.12.004; RA Deschauer M., Hudson G., Mueller T., Taylor R.W., Chinnery P.F., Zierz S.; RT "A novel ANT1 gene mutation with probable germline mosaicism in autosomal RT dominant progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 15:311-315(2005). RN [26] RP VARIANTS PEOA2 PRO-98 AND PRO-114. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [27] RP VARIANT MTDPS12B PRO-236. RX PubMed=25732997; DOI=10.1007/8904_2015_409; RA Koerver-Keularts I.M., de Visser M., Bakker H.D., Wanders R.J., RA Vansenne F., Scholte H.R., Dorland L., Nicolaes G.A., Spaapen L.M., RA Smeets H.J., Hendrickx A.T., van den Bosch B.J.; RT "Two novel mutations in the SLC25A4 gene in a patient with mitochondrial RT myopathy."; RL JIMD Rep. 22:39-45(2015). RN [28] RP VARIANT GLN-33, CHARACTERIZATION OF VARIANT GLN-33, AND FUNCTION. RX PubMed=30046662; DOI=10.1212/nxg.0000000000000256; RA King M.S., Thompson K., Hopton S., He L., Kunji E.R.S., Taylor R.W., RA Ortiz-Gonzalez X.R.; RT "Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to RT include mild myopathy."; RL Neurol. Genet. 4:e256-e256(2018). CC -!- FUNCTION: ADP:ATP antiporter that mediates import of ADP into the CC mitochondrial matrix for ATP synthesis, and export of ATP out to fuel CC the cell (PubMed:21586654, PubMed:27693233, PubMed:23173940, CC PubMed:30046662). Cycles between the cytoplasmic-open state (c-state) CC and the matrix-open state (m-state): operates by the alternating access CC mechanism with a single substrate-binding site intermittently exposed CC to either the cytosolic (c-state) or matrix (m-state) side of the inner CC mitochondrial membrane (By similarity). Substrate exchange across the CC membrane occurs consecutively with one substrate being transported CC first, then dissociating from the substrate binding site before the CC second substrate binds for transport in the opposite direction CC (PubMed:37278158). In addition to its ADP:ATP antiporter activity, also CC involved in mitochondrial uncoupling and mitochondrial permeability CC transition pore (mPTP) activity (PubMed:31883789). Plays a role in CC mitochondrial uncoupling by acting as a proton transporter: proton CC transport uncouples the proton flows via the electron transport chain CC and ATP synthase to reduce the efficiency of ATP production and cause CC mitochondrial thermogenesis (By similarity). Proton transporter CC activity is inhibited by ADP:ATP antiporter activity, suggesting that CC SLC25A4/ANT1 acts as a master regulator of mitochondrial energy output CC by maintaining a delicate balance between ATP production (ADP:ATP CC antiporter activity) and thermogenesis (proton transporter activity) CC (By similarity). Proton transporter activity requires free fatty acids CC as cofactor, but does not transport it (By similarity). Also plays a CC key role in mPTP opening, a non-specific pore that enables free passage CC of the mitochondrial membranes to solutes of up to 1.5 kDa, and which CC contributes to cell death (PubMed:31883789). It is however unclear if CC SLC25A4/ANT1 constitutes a pore-forming component of mPTP or regulates CC it (By similarity). Acts as a regulator of mitophagy independently of CC ADP:ATP antiporter activity: promotes mitophagy via interaction with CC TIMM44, leading to inhibit the presequence translocase TIMM23, thereby CC promoting stabilization of PINK1 (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962, CC ECO:0000269|PubMed:21586654, ECO:0000269|PubMed:23173940, CC ECO:0000269|PubMed:27693233, ECO:0000269|PubMed:31883789, CC ECO:0000269|PubMed:37278158}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ADP(in) + ATP(out) = ADP(out) + ATP(in); Xref=Rhea:RHEA:34999, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:456216; CC Evidence={ECO:0000269|PubMed:21586654, ECO:0000269|PubMed:23173940}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+)(in) = H(+)(out); Xref=Rhea:RHEA:34979, ChEBI:CHEBI:15378; CC Evidence={ECO:0000250|UniProtKB:P48962}; CC -!- ACTIVITY REGULATION: The matrix-open state (m-state) is inhibited by CC the membrane-permeable bongkrekic acid (BKA) PubMed:23173940. The CC cytoplasmic-open state (c-state) is inhibited by the membrane- CC impermeable toxic inhibitor carboxyatractyloside (CATR) CC (PubMed:21586654, PubMed:23173940). Proton transporter activity is CC inhibited by ADP:ATP antiporter activity (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P48962, CC ECO:0000269|PubMed:21586654}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=23.7 uM for ATP {ECO:0000269|PubMed:23173940}; CC Vmax=14.6 nmol/min/mg enzyme for ATP uptake CC {ECO:0000269|PubMed:23173940}; CC -!- SUBUNIT: Monomer (By similarity). Found in a complex with ARL2, ARL2BP CC and SLC25A4/ANT1 (By similarity). Interacts with ARL2BP (By CC similarity). Interacts with ARHGAP11B, thereby inhibiting the CC mitochondrial permeability transition pore (mPTP) (PubMed:31883789). CC Interacts with TIMM44; leading to inhibit the presequence translocase CC TIMM23, thereby promoting stabilization of PINK1 (By similarity). CC {ECO:0000250|UniProtKB:G2QNH0, ECO:0000250|UniProtKB:P02722, CC ECO:0000250|UniProtKB:P48962, ECO:0000269|PubMed:31883789}. CC -!- SUBUNIT: (Microbial infection) Interacts with HIV-1 Vpr. CC {ECO:0000269|PubMed:16120388}. CC -!- INTERACTION: CC P12235; Q5S007: LRRK2; NbExp=2; IntAct=EBI-359074, EBI-5323863; CC P12235; P22736-1: NR4A1; NbExp=2; IntAct=EBI-359074, EBI-16085263; CC P12235; P12236: SLC25A6; NbExp=2; IntAct=EBI-359074, EBI-356254; CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane CC {ECO:0000269|PubMed:21586654}; Multi-pass membrane protein CC {ECO:0000255}. Membrane {ECO:0000269|PubMed:27641616}; Multi-pass CC membrane protein {ECO:0000255}. Note=The complex formed with ARL2BP, CC ARL2 and SLC25A4/ANT1 is expressed in mitochondria (By similarity). May CC localize to non-mitochondrial membranes (PubMed:27641616). CC {ECO:0000250|UniProtKB:P48962, ECO:0000269|PubMed:27641616}. CC -!- TISSUE SPECIFICITY: Expressed in erythrocytes (at protein level). CC {ECO:0000269|PubMed:27641616}. CC -!- DOMAIN: The transmembrane helices are not perpendicular to the plane of CC the membrane, but cross the membrane at an angle. Odd-numbered CC transmembrane helices exhibit a sharp kink, due to the presence of a CC conserved proline residue. {ECO:0000250|UniProtKB:P02722}. CC -!- PTM: Under cell death induction, transglutaminated by TGM2. CC Transglutamination leads to formation of covalent cross-links between a CC glutamine and the epsilon-amino group of a lysine residue, forming CC polymers. {ECO:0000250|UniProtKB:P48962}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 2 (PEOA2) [MIM:609283]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:10926541, CC ECO:0000269|PubMed:11756613, ECO:0000269|PubMed:12112115, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:15792871, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:21586654, CC ECO:0000269|PubMed:27693233}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type CC (MTDPS12B) [MIM:615418]: An autosomal recessive mitochondrial disorder CC characterized by childhood onset of slowly progressive hypertrophic CC cardiomyopathy and generalized skeletal myopathy resulting in exercise CC intolerance and, in some patients, muscle weakness and atrophy. CC Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and CC accumulation of abnormal mitochondria. {ECO:0000269|PubMed:16155110, CC ECO:0000269|PubMed:22187496, ECO:0000269|PubMed:25732997, CC ECO:0000269|PubMed:27693233}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type CC (MTDPS12A) [MIM:617184]: An autosomal dominant mitochondrial disorder CC characterized by severe hypotonia due to mitochondrial dysfunction CC apparent at birth. Affected infants have respiratory insufficiency CC requiring mechanical ventilation and have poor or no motor development. CC Many die in infancy, and those that survive have profound hypotonia CC with significant muscle weakness and inability to walk independently. CC Some patients develop hypertrophic cardiomyopathy. Muscle samples show CC mtDNA depletion and severe combined mitochondrial respiratory chain CC deficiencies. {ECO:0000269|PubMed:27693233}. Note=The disease is caused CC by variants affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the mitochondrial carrier (TC 2.A.29) family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; J02966; AAA61223.1; -; mRNA. DR EMBL; J04982; AAA51736.1; -; Genomic_DNA. DR EMBL; HQ206346; ADP92294.1; -; Genomic_DNA. DR EMBL; HQ206347; ADP92295.1; -; Genomic_DNA. DR EMBL; HQ206348; ADP92296.1; -; Genomic_DNA. DR EMBL; HQ206349; ADP92297.1; -; Genomic_DNA. DR EMBL; HQ206350; ADP92298.1; -; Genomic_DNA. DR EMBL; HQ206351; ADP92299.1; -; Genomic_DNA. DR EMBL; HQ206352; ADP92300.1; -; Genomic_DNA. DR EMBL; HQ206353; ADP92301.1; -; Genomic_DNA. DR EMBL; HQ206354; ADP92302.1; -; Genomic_DNA. DR EMBL; HQ206355; ADP92303.1; -; Genomic_DNA. DR EMBL; HQ206356; ADP92304.1; -; Genomic_DNA. DR EMBL; HQ206357; ADP92305.1; -; Genomic_DNA. DR EMBL; HQ206358; ADP92306.1; -; Genomic_DNA. DR EMBL; HQ206359; ADP92307.1; -; Genomic_DNA. DR EMBL; HQ206360; ADP92308.1; -; Genomic_DNA. DR EMBL; HQ206361; ADP92309.1; -; Genomic_DNA. DR EMBL; HQ206362; ADP92310.1; -; Genomic_DNA. DR EMBL; HQ206363; ADP92311.1; -; Genomic_DNA. DR EMBL; HQ206364; ADP92312.1; -; Genomic_DNA. DR EMBL; HQ206365; ADP92313.1; -; Genomic_DNA. DR EMBL; HQ206366; ADP92314.1; -; Genomic_DNA. DR EMBL; HQ206367; ADP92315.1; -; Genomic_DNA. DR EMBL; HQ206368; ADP92316.1; -; Genomic_DNA. DR EMBL; HQ206369; ADP92317.1; -; Genomic_DNA. DR EMBL; HQ206370; ADP92318.1; -; Genomic_DNA. DR EMBL; HQ206371; ADP92319.1; -; Genomic_DNA. DR EMBL; HQ206372; ADP92320.1; -; Genomic_DNA. DR EMBL; HQ206373; ADP92321.1; -; Genomic_DNA. DR EMBL; HQ206374; ADP92322.1; -; Genomic_DNA. DR EMBL; HQ206375; ADP92323.1; -; Genomic_DNA. DR EMBL; HQ206376; ADP92324.1; -; Genomic_DNA. DR EMBL; HQ206377; ADP92325.1; -; Genomic_DNA. DR EMBL; HQ206378; ADP92326.1; -; Genomic_DNA. DR EMBL; HQ206379; ADP92327.1; -; Genomic_DNA. DR EMBL; HQ206380; ADP92328.1; -; Genomic_DNA. DR EMBL; HQ206381; ADP92329.1; -; Genomic_DNA. DR EMBL; HQ206382; ADP92330.1; -; Genomic_DNA. DR EMBL; HQ206383; ADP92331.1; -; Genomic_DNA. DR EMBL; HQ206384; ADP92332.1; -; Genomic_DNA. DR EMBL; HQ206385; ADP92333.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04655.1; -; Genomic_DNA. DR EMBL; CH471056; EAX04656.1; -; Genomic_DNA. DR EMBL; BC008664; AAH08664.1; -; mRNA. DR EMBL; BC061589; AAH61589.1; -; mRNA. DR EMBL; BC063643; AAH63643.1; -; mRNA. DR EMBL; J03593; AAA36751.1; -; mRNA. DR CCDS; CCDS34114.1; -. DR PIR; A44778; A44778. DR RefSeq; NP_001142.2; NM_001151.4. DR AlphaFoldDB; P12235; -. DR SMR; P12235; -. DR BioGRID; 106788; 352. DR DIP; DIP-33116N; -. DR FunCoup; P12235; 1978. DR IntAct; P12235; 125. DR MINT; P12235; -. DR STRING; 9606.ENSP00000281456; -. DR DrugBank; DB01736; [3-(Dodecanoylamino)Propyl](Hydroxy)Dimethylammonium. DR DrugBank; DB00171; ATP. DR DrugBank; DB02426; Carboxyatractyloside. DR DrugBank; DB00720; Clodronic acid. DR DrugBank; DB04178; Di-Stearoyl-3-Sn-Phosphatidylcholine. DR DrugBank; DB01077; Etidronic acid. DR DrugBank; DB03429; Tetrastearoyl cardiolipin. DR DrugCentral; P12235; -. DR MoonProt; P12235; -. DR TCDB; 2.A.29.1.2; the mitochondrial carrier (mc) family. DR GlyGen; P12235; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P12235; -. DR MetOSite; P12235; -. DR PhosphoSitePlus; P12235; -. DR SwissPalm; P12235; -. DR BioMuta; SLC25A4; -. DR DMDM; 113455; -. DR jPOST; P12235; -. DR MassIVE; P12235; -. DR PaxDb; 9606-ENSP00000281456; -. DR PeptideAtlas; P12235; -. DR ProteomicsDB; 52836; -. DR Pumba; P12235; -. DR TopDownProteomics; P12235; -. DR Antibodypedia; 28911; 156 antibodies from 24 providers. DR DNASU; 291; -. DR Ensembl; ENST00000281456.11; ENSP00000281456.5; ENSG00000151729.12. DR GeneID; 291; -. DR KEGG; hsa:291; -. DR MANE-Select; ENST00000281456.11; ENSP00000281456.5; NM_001151.4; NP_001142.2. DR UCSC; uc003ixd.4; human. DR AGR; HGNC:10990; -. DR ClinPGx; PA35866; -. DR CTD; 291; -. DR DisGeNET; 291; -. DR GeneCards; SLC25A4; -. DR HGNC; HGNC:10990; SLC25A4. DR HPA; ENSG00000151729; Group enriched (heart muscle, skeletal muscle, tongue). DR MalaCards; SLC25A4; -. DR MIM; 103220; gene. DR MIM; 609283; phenotype. DR MIM; 615418; phenotype. DR MIM; 617184; phenotype. DR OpenTargets; ENSG00000151729; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1369; Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome. DR VEuPathDB; HostDB:ENSG00000151729; -. DR eggNOG; KOG0749; Eukaryota. DR GeneTree; ENSGT00940000154622; -. DR InParanoid; P12235; -. DR OMA; HPAMYQR; -. DR OrthoDB; 270584at2759; -. DR PAN-GO; P12235; 4 GO annotations based on evolutionary models. DR PhylomeDB; P12235; -. DR PathwayCommons; P12235; -. DR Reactome; R-HSA-1268020; Mitochondrial protein import. DR Reactome; R-HSA-166187; Mitochondrial Uncoupling. DR Reactome; R-HSA-180897; Vpr-mediated induction of apoptosis by mitochondrial outer membrane permeabilization. DR Reactome; R-HSA-83936; Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane. DR SignaLink; P12235; -. DR SIGNOR; P12235; -. DR Agora; ENSG00000151729; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 291; 14 hits in 1168 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR CD-CODE; FB4E32DD; Presynaptic clusters and postsynaptic densities. DR ChiTaRS; SLC25A4; human. DR GeneWiki; SLC25A4; -. DR GenomeRNAi; 291; -. DR Pharos; P12235; Tbio. DR PRO; PR:P12235; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P12235; protein. DR Bgee; ENSG00000151729; Expressed in left ventricle myocardium and 209 other cell types or tissues. DR ExpressionAtlas; P12235; baseline and differential. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; ISS:UniProtKB. DR GO; GO:0005757; C:mitochondrial permeability transition pore complex; ISS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0015207; F:adenine transmembrane transporter activity; TAS:ProtInc. DR GO; GO:0005471; F:ATP:ADP antiporter activity; IDA:UniProtKB. DR GO; GO:0017077; F:oxidative phosphorylation uncoupler activity; ISS:UniProtKB. DR GO; GO:0015078; F:proton transmembrane transporter activity; TAS:Reactome. DR GO; GO:1990845; P:adaptive thermogenesis; ISS:UniProtKB. DR GO; GO:0015866; P:ADP transport; IMP:UniProtKB. DR GO; GO:0008637; P:apoptotic mitochondrial changes; IEA:Ensembl. DR GO; GO:0006091; P:generation of precursor metabolites and energy; TAS:ProtInc. DR GO; GO:0140021; P:mitochondrial ADP transmembrane transport; IDA:UniProtKB. DR GO; GO:1990544; P:mitochondrial ATP transmembrane transport; IDA:UniProtKB. DR GO; GO:1901029; P:negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IBA:GO_Central. DR GO; GO:0060546; P:negative regulation of necroptotic process; IMP:BHF-UCL. DR GO; GO:1901526; P:positive regulation of mitophagy; ISS:UniProtKB. DR GO; GO:0046902; P:regulation of mitochondrial membrane permeability; ISS:UniProtKB. DR FunFam; 1.50.40.10:FF:000002; Putative ADP/ATP translocase 2-like; 1. DR Gene3D; 1.50.40.10; Mitochondrial carrier domain; 1. DR InterPro; IPR002113; ADT_euk_type. DR InterPro; IPR002067; MCP. DR InterPro; IPR023395; MCP_dom_sf. DR InterPro; IPR018108; MCP_transmembrane. DR PANTHER; PTHR45635; ADP,ATP CARRIER PROTEIN 1-RELATED-RELATED; 1. DR PANTHER; PTHR45635:SF32; ADP_ATP TRANSLOCASE 1; 1. DR Pfam; PF00153; Mito_carr; 3. DR PRINTS; PR00927; ADPTRNSLCASE. DR PRINTS; PR00926; MITOCARRIER. DR SUPFAM; SSF103506; Mitochondrial carrier; 1. DR PROSITE; PS50920; SOLCAR; 3. PE 1: Evidence at protein level; KW Acetylation; Antiport; ATP-binding; Cardiomyopathy; KW Direct protein sequencing; Disease variant; Host-virus interaction; KW Membrane; Methylation; Mitochondrion; Mitochondrion inner membrane; KW Nucleotide-binding; Phosphoprotein; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Repeat; S-nitrosylation; Transmembrane; KW Transmembrane helix; Transport. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000269|Ref.8" FT CHAIN 2..298 FT /note="ADP/ATP translocase 1" FT /id="PRO_0000090574" FT TOPO_DOM 2..7 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 8..37 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 38..74 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 75..99 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 100..109 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 110..130 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 131..178 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 179..199 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 200..210 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT TRANSMEM 211..231 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 232..273 FT /note="Mitochondrial matrix" FT /evidence="ECO:0000305" FT TRANSMEM 274..291 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:P02722" FT TOPO_DOM 292..298 FT /note="Mitochondrial intermembrane" FT /evidence="ECO:0000305" FT REPEAT 6..98 FT /note="Solcar 1" FT REPEAT 111..201 FT /note="Solcar 2" FT REPEAT 212..297 FT /note="Solcar 3" FT REGION 235..240 FT /note="Important for transport activity" FT /evidence="ECO:0000269|PubMed:27693233" FT MOTIF 235..240 FT /note="Nucleotide carrier signature motif" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 80 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 92 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT BINDING 235 FT /ligand="ADP" FT /ligand_id="ChEBI:CHEBI:456216" FT /evidence="ECO:0000250|UniProtKB:P02722" FT MOD_RES 2 FT /note="N-acetylglycine" FT /evidence="ECO:0000269|Ref.8" FT MOD_RES 7 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 52 FT /note="N6,N6,N6-trimethyllysine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 147 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT MOD_RES 160 FT /note="S-nitrosocysteine" FT /evidence="ECO:0000250|UniProtKB:Q05962" FT MOD_RES 245 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT MOD_RES 272 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P48962" FT VARIANT 33 FT /note="K -> Q (found in a patient with mild childhood-onset FT myopathy without evidence of other clinical features such FT as cardiomyopathy, encephalopathy or ophthalmoplegia; FT likely pathogenic; abolishes ADP transport)" FT /evidence="ECO:0000269|PubMed:30046662" FT /id="VAR_090742" FT VARIANT 80 FT /note="R -> H (in MTDPS12A; decreased function in ADP FT transport; dbSNP:rs886041081)" FT /evidence="ECO:0000269|PubMed:27693233" FT /id="VAR_078071" FT VARIANT 90 FT /note="A -> D (in PEOA2; decreased function in ADP FT transport)" FT /evidence="ECO:0000269|PubMed:15792871, FT ECO:0000269|PubMed:27693233" FT /id="VAR_038814" FT VARIANT 98 FT /note="L -> P (in PEOA2; decreased function in ADP FT transport; dbSNP:rs104893876)" FT /evidence="ECO:0000269|PubMed:11756613, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:27693233" FT /id="VAR_022459" FT VARIANT 104 FT /note="D -> G (in PEOA2; decreased function in ADP FT transport; dbSNP:rs28999114)" FT /evidence="ECO:0000269|PubMed:12112115, FT ECO:0000269|PubMed:27693233" FT /id="VAR_022460" FT VARIANT 114 FT /note="A -> P (in PEOA2; decreased function in ADP FT transport; inverted direction of ADP:ATP transport, with FT ATP entering the mitochondrial matrix; dbSNP:rs104893873)" FT /evidence="ECO:0000269|PubMed:10926541, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:21586654, FT ECO:0000269|PubMed:27693233" FT /id="VAR_012111" FT VARIANT 123 FT /note="A -> D (in MTDPS12B; loss of function in ADP FT transport; dbSNP:rs121912683)" FT /evidence="ECO:0000269|PubMed:16155110, FT ECO:0000269|PubMed:27693233" FT /id="VAR_038815" FT VARIANT 235 FT /note="R -> G (in MTDPS12A; severely decreased function in FT ADP transport; dbSNP:rs886041082)" FT /evidence="ECO:0000269|PubMed:27693233" FT /id="VAR_078072" FT VARIANT 236 FT /note="R -> P (in MTDPS12B; loss of function in ADP FT transport; dbSNP:rs770816416)" FT /evidence="ECO:0000269|PubMed:25732997, FT ECO:0000269|PubMed:27693233" FT /id="VAR_078073" FT VARIANT 289 FT /note="V -> M (in PEOA2; inverted direction of ADP:ATP FT transport, with ATP entering the mitochondrial matrix; FT dbSNP:rs104893874)" FT /evidence="ECO:0000269|PubMed:10926541, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:21586654" FT /id="VAR_012112" FT CONFLICT 16 FT /note="G -> A (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" FT CONFLICT 147..149 FT /note="KGA -> RR (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" FT CONFLICT 227 FT /note="V -> L (in Ref. 1; AAA61223)" FT /evidence="ECO:0000305" SQ SEQUENCE 298 AA; 33064 MW; 59F0DFAEC4E7CFBB CRC64; MGDHAWSFLK DFLAGGVAAA VSKTAVAPIE RVKLLLQVQH ASKQISAEKQ YKGIIDCVVR IPKEQGFLSF WRGNLANVIR YFPTQALNFA FKDKYKQLFL GGVDRHKQFW RYFAGNLASG GAAGATSLCF VYPLDFARTR LAADVGKGAA QREFHGLGDC IIKIFKSDGL RGLYQGFNVS VQGIIIYRAA YFGVYDTAKG MLPDPKNVHI FVSWMIAQSV TAVAGLVSYP FDTVRRRMMM QSGRKGADIM YTGTVDCWRK IAKDEGAKAF FKGAWSNVLR GMGGAFVLVL YDEIKKYV // ID ATX2_HUMAN Reviewed; 1313 AA. AC Q99700; A6NLD4; Q24JQ7; Q6ZQZ7; Q99493; DT 13-SEP-2004, integrated into UniProtKB/Swiss-Prot. DT 25-NOV-2008, sequence version 2. DT 28-JAN-2026, entry version 204. DE RecName: Full=Ataxin-2; DE AltName: Full=Spinocerebellar ataxia type 2 protein; DE AltName: Full=Trinucleotide repeat-containing gene 13 protein; GN Name=ATXN2; Synonyms=ATX2, SCA2, TNRC13; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896555; DOI=10.1038/ng1196-269; RA Pulst S.-M., Nechiporuk A., Nechiporuk T., Gispert S., Chen X.-N., RA Lopes-Cendes I., Pearlman S., Starkman S., Orozco-Diaz G., Lunkes A., RA DeJong P., Rouleau G.A., Auburger G., Korenberg J.R., Figueroa C., RA Sahba S.; RT "Moderate expansion of a normally biallelic trinucleotide repeat in RT spinocerebellar ataxia type 2."; RL Nat. Genet. 14:269-276(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), POLYMORPHISM, INVOLVEMENT IN SCA2, RP AND TISSUE SPECIFICITY. RX PubMed=8896556; DOI=10.1038/ng1196-277; RA Sanpei K., Takano H., Igarashi S., Sato T., Oyake M., Sasaki H., RA Wakisaka A., Tashiro K., Ishida Y., Ikeuchi T., Koide R., Saito M., RA Sato A., Tanaka T., Hanyu S., Takiyama Y., Nishizawa M., Shimizu N., RA Nomura Y., Segawa M., Iwabuchi K., Eguchi I., Tanaka H., Takahashi H., RA Tsuji S.; RT "Identification of the spinocerebellar ataxia type 2 gene using a direct RT identification of repeat expansion and cloning technique, DIRECT."; RL Nat. Genet. 14:277-284(1996). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16541075; DOI=10.1038/nature04569; RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., RA Gibbs R.A.; RT "The finished DNA sequence of human chromosome 12."; RL Nature 440:346-351(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5). RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 81-1313 (ISOFORM 2), POLYMORPHISM, RP INVOLVEMENT IN SCA2, TISSUE SPECIFICITY, AND VARIANT VAL-107. RX PubMed=8896557; DOI=10.1038/ng1196-285; RA Imbert G., Saudou F., Yvert G., Devys D., Trottier Y., Garnier J.-M., RA Weber C., Mandel J.-L., Cancel G., Abbas N., Duerr A., Didierjean O., RA Stevanin G., Agid Y., Brice A.; RT "Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high RT sensitivity to expanded CAG/glutamine repeats."; RL Nat. Genet. 14:285-291(1996). RN [7] RP ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY. RX PubMed=9480749; DOI=10.1006/geno.1997.5131; RA Sahba S., Nechiporuk A., Figueroa K.P., Nechiporuk T., Pulst S.-M.; RT "Genomic structure of the human gene for spinocerebellar ataxia type 2 RT (SCA2) on chromosome 12q24.1."; RL Genomics 47:359-364(1998). RN [8] RP INTERACTION WITH RBFOX1. RX PubMed=10814712; DOI=10.1093/hmg/9.9.1303; RA Shibata H., Huynh D.P., Pulst S.-M.; RT "A novel protein with RNA-binding motifs interacts with ataxin-2."; RL Hum. Mol. Genet. 9:1303-1313(2000). RN [9] RP INTERACTION WITH POLYRIBOSOMES. RX PubMed=16835262; DOI=10.1093/hmg/ddl173; RA Satterfield T.F., Pallanck L.J.; RT "Ataxin-2 and its Drosophila homolog, ATX2, physically assemble with RT polyribosomes."; RL Hum. Mol. Genet. 15:2523-2532(2006). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=16964243; DOI=10.1038/nbt1240; RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.; RT "A probability-based approach for high-throughput protein phosphorylation RT analysis and site localization."; RL Nat. Biotechnol. 24:1285-1292(2006). RN [11] RP FUNCTION, AND INTERACTION WITH EGFR; SH3GL2 AND SH3GL3. RX PubMed=18602463; DOI=10.1016/j.cellsig.2008.05.018; RA Nonis D., Schmidt M.H., van de Loo S., Eich F., Dikic I., Nowock J., RA Auburger G.; RT "Ataxin-2 associates with the endocytosis complex and affects EGF receptor RT trafficking."; RL Cell. Signal. 20:1725-1739(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-554; SER-684; RP THR-741; SER-857; SER-861; SER-888 AND SER-889, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [15] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-684, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [16] RP INTERACTION WITH TARDBP, INVOLVEMENT IN ALS13, AND POLY-GLN REPEAT RP EXPANSION. RX PubMed=20740007; DOI=10.1038/nature09320; RA Elden A.C., Kim H.J., Hart M.P., Chen-Plotkin A.S., Johnson B.S., Fang X., RA Armakola M., Geser F., Greene R., Lu M.M., Padmanabhan A., Clay-Falcone D., RA McCluskey L., Elman L., Juhr D., Gruber P.J., Rub U., Auburger G., RA Trojanowski J.Q., Lee V.M., Van Deerlin V.M., Bonini N.M., Gitler A.D.; RT "Ataxin-2 intermediate-length polyglutamine expansions are associated with RT increased risk for ALS."; RL Nature 466:1069-1075(2010). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-393; SER-684 AND SER-784, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-784; SER-861 AND SER-865, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [20] RP INTERACTION WITH ATXN2L. RX PubMed=23209657; DOI=10.1371/journal.pone.0050134; RA Kaehler C., Isensee J., Nonhoff U., Terrey M., Hucho T., Lehrach H., RA Krobitsch S.; RT "Ataxin-2-like is a regulator of stress granules and processing bodies."; RL PLoS ONE 7:E50134-E50134(2012). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-466; SER-478; SER-508; RP SER-624; SER-642; SER-684; SER-772; SER-784 AND SER-889, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-624 AND SER-728, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP METHYLATION [LARGE SCALE ANALYSIS] AT ARG-640, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Colon carcinoma; RX PubMed=24129315; DOI=10.1074/mcp.o113.027870; RA Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M., RA Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V., RA Bedford M.T., Comb M.J.; RT "Immunoaffinity enrichment and mass spectrometry analysis of protein RT methylation."; RL Mol. Cell. Proteomics 13:372-387(2014). RN [24] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-893, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). CC -!- FUNCTION: Involved in EGFR trafficking, acting as negative regulator of CC endocytic EGFR internalization at the plasma membrane. CC {ECO:0000269|PubMed:18602463}. CC -!- SUBUNIT: Monomer (By similarity). Can also form homodimers (By CC similarity). Interacts with TARDBP; the interaction is RNA-dependent CC (PubMed:20740007). Interacts with RBFOX1 (PubMed:10814712). Interacts CC with polyribosomes (PubMed:16835262). Interacts with SH3GL2 and SH3GL3 CC (PubMed:18602463). Interacts with SH3KBP1 and CBL (By similarity). CC Interacts with EGFR (PubMed:18602463). Interacts with ATXN2L CC (PubMed:23209657). {ECO:0000250|UniProtKB:O70305, CC ECO:0000269|PubMed:10814712, ECO:0000269|PubMed:16835262, CC ECO:0000269|PubMed:18602463, ECO:0000269|PubMed:20740007, CC ECO:0000269|PubMed:23209657}. CC -!- INTERACTION: CC Q99700; P54253: ATXN1; NbExp=4; IntAct=EBI-697691, EBI-930964; CC Q99700; P26196: DDX6; NbExp=14; IntAct=EBI-697691, EBI-351257; CC Q99700; Q13283: G3BP1; NbExp=4; IntAct=EBI-697691, EBI-1047359; CC Q99700; P11940: PABPC1; NbExp=8; IntAct=EBI-697691, EBI-81531; CC Q99700; Q99962: SH3GL2; NbExp=9; IntAct=EBI-697691, EBI-77938; CC Q99700; Q99963: SH3GL3; NbExp=11; IntAct=EBI-697691, EBI-473910; CC Q99700; Q13148: TARDBP; NbExp=3; IntAct=EBI-697691, EBI-372899; CC Q99700-5; P54253: ATXN1; NbExp=6; IntAct=EBI-25891409, EBI-930964; CC Q99700-5; P46379-2: BAG6; NbExp=3; IntAct=EBI-25891409, EBI-10988864; CC Q99700-5; Q9BTH3: BIN1; NbExp=3; IntAct=EBI-25891409, EBI-25891390; CC Q99700-5; Q8WUW1: BRK1; NbExp=3; IntAct=EBI-25891409, EBI-2837444; CC Q99700-5; P20963: CD247; NbExp=3; IntAct=EBI-25891409, EBI-1165705; CC Q99700-5; P11940: PABPC1; NbExp=3; IntAct=EBI-25891409, EBI-81531; CC Q99700-5; Q9NWB1-5: RBFOX1; NbExp=3; IntAct=EBI-25891409, EBI-12123390; CC Q99700-5; Q8IVP1: SH3GL3; NbExp=3; IntAct=EBI-25891409, EBI-6503765; CC Q99700-5; Q9UJZ1: STOML2; NbExp=3; IntAct=EBI-25891409, EBI-1044428; CC Q99700-5; P55854: SUMO3; NbExp=3; IntAct=EBI-25891409, EBI-474067; CC Q99700-5; P40337-2: VHL; NbExp=3; IntAct=EBI-25891409, EBI-12157263; CC Q99700-5; Q96E88; NbExp=3; IntAct=EBI-25891409, EBI-10976904; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; CC IsoId=Q99700-1; Sequence=Displayed; CC Name=2; CC IsoId=Q99700-2; Sequence=VSP_011575, VSP_011577; CC Name=3; CC IsoId=Q99700-3; Sequence=VSP_011574, VSP_011576, VSP_011578, CC VSP_011579, VSP_011580, VSP_011581; CC Name=4; CC IsoId=Q99700-4; Sequence=VSP_011582; CC Name=5; CC IsoId=Q99700-5; Sequence=VSP_057285, VSP_057286, VSP_057287; CC -!- TISSUE SPECIFICITY: Expressed in the brain, heart, liver, skeletal CC muscle, pancreas and placenta. Isoform 1 is predominant in the brain CC and spinal cord. Isoform 4 is more abundant in the cerebellum. In the CC brain, broadly expressed in the amygdala, caudate nucleus, corpus CC callosum, hippocampus, hypothalamus, substantia nigra, subthalamic CC nucleus and thalamus. {ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557, CC ECO:0000269|PubMed:9480749}. CC -!- POLYMORPHISM: The poly-Gln region of ATXN2 is polymorphic: 17 to 29 CC repeats are found in the normal population. Higher numbers of repeats CC result in different disease phenotypes depending on the length of the CC expansion. {ECO:0000269|PubMed:20740007, ECO:0000269|PubMed:8896555, CC ECO:0000269|PubMed:8896556, ECO:0000269|PubMed:8896557}. CC -!- DISEASE: Spinocerebellar ataxia 2 (SCA2) [MIM:183090]: Spinocerebellar CC ataxia is a clinically and genetically heterogeneous group of CC cerebellar disorders. Patients show progressive incoordination of gait CC and often poor coordination of hands, speech and eye movements, due to CC cerebellum degeneration with variable involvement of the brainstem and CC spinal cord. SCA2 belongs to the autosomal dominant cerebellar ataxias CC type I (ADCA I) which are characterized by cerebellar ataxia in CC combination with additional clinical features like optic atrophy, CC ophthalmoplegia, bulbar and extrapyramidal signs, peripheral neuropathy CC and dementia. SCA2 is characterized by hyporeflexia, myoclonus and CC action tremor and dopamine-responsive parkinsonism. In some patients, CC SCA2 presents as pure familial parkinsonism without cerebellar signs. CC {ECO:0000269|PubMed:8896555, ECO:0000269|PubMed:8896556, CC ECO:0000269|PubMed:8896557}. Note=The disease is caused by variants CC affecting the gene represented in this entry. SCA2 is caused by CC expansion of a CAG repeat resulting in about 36 to 52 repeats in some CC patients. Longer expansions result in earlier the expansion, onset of CC the disease. CC -!- DISEASE: Amyotrophic lateral sclerosis 13 (ALS13) [MIM:183090]: A CC neurodegenerative disorder affecting upper motor neurons in the brain CC and lower motor neurons in the brain stem and spinal cord, resulting in CC fatal paralysis. Sensory abnormalities are absent. The pathologic CC hallmarks of the disease include pallor of the corticospinal tract due CC to loss of motor neurons, presence of ubiquitin-positive inclusions CC within surviving motor neurons, and deposition of pathologic CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to CC be multifactorial, involving both genetic and environmental factors. CC The disease is inherited in 5-10% of the cases. CC {ECO:0000269|PubMed:20740007}. Note=Disease susceptibility is CC associated with variants affecting the gene represented in this entry. CC An increased risk for developing amyotrophic lateral sclerosis seems to CC be conferred by CAG repeat intermediate expansions greater than 23 but CC below the threshold for developing spinocerebellar ataxia. CC -!- SIMILARITY: Belongs to the ataxin-2 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U70323; AAB19200.1; -; mRNA. DR EMBL; AK128613; BAC87528.1; -; mRNA. DR EMBL; AC002395; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC137055; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; KF455720; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC114546; AAI14547.1; -; mRNA. DR EMBL; Y08262; CAA69589.1; -; mRNA. DR CCDS; CCDS81738.1; -. [Q99700-5] DR RefSeq; NP_001297052.1; NM_001310123.1. [Q99700-5] DR RefSeq; NP_002964.4; NM_002973.4. DR PDB; 3KTR; X-ray; 1.70 A; B=912-928. DR PDBsum; 3KTR; -. DR AlphaFoldDB; Q99700; -. DR SMR; Q99700; -. DR BioGRID; 112218; 327. DR DIP; DIP-33372N; -. DR ELM; Q99700; -. DR FunCoup; Q99700; 1901. DR IntAct; Q99700; 166. DR MINT; Q99700; -. DR STRING; 9606.ENSP00000446576; -. DR BindingDB; Q99700; -. DR ChEMBL; CHEMBL1795085; -. DR GlyCosmos; Q99700; 7 sites, 1 glycan. DR GlyGen; Q99700; 26 sites, 1 O-linked glycan (23 sites). DR iPTMnet; Q99700; -. DR MetOSite; Q99700; -. DR PhosphoSitePlus; Q99700; -. DR SwissPalm; Q99700; -. DR BioMuta; ATXN2; -. DR DMDM; 215273941; -. DR jPOST; Q99700; -. DR MassIVE; Q99700; -. DR PaxDb; 9606-ENSP00000366843; -. DR PeptideAtlas; Q99700; -. DR ProteomicsDB; 61268; -. DR ProteomicsDB; 78409; -. [Q99700-1] DR ProteomicsDB; 78410; -. [Q99700-2] DR ProteomicsDB; 78412; -. [Q99700-4] DR Pumba; Q99700; -. DR Antibodypedia; 18563; 277 antibodies from 36 providers. DR DNASU; 6311; -. DR Ensembl; ENST00000535949.5; ENSP00000439338.1; ENSG00000204842.19. [Q99700-5] DR Ensembl; ENST00000550104.5; ENSP00000446576.2; ENSG00000204842.19. [Q99700-1] DR Ensembl; ENST00000616825.4; ENSP00000481448.1; ENSG00000204842.19. [Q99700-5] DR GeneID; 6311; -. DR KEGG; hsa:6311; -. DR UCSC; uc001tsj.3; human. [Q99700-1] DR AGR; HGNC:10555; -. DR ClinPGx; PA34968; -. DR CTD; 6311; -. DR DisGeNET; 6311; -. DR GeneCards; ATXN2; -. DR GeneReviews; ATXN2; -. DR HGNC; HGNC:10555; ATXN2. DR HPA; ENSG00000204842; Low tissue specificity. DR MalaCards; ATXN2; -. DR MIM; 183090; phenotype. DR MIM; 601517; gene. DR OpenTargets; ENSG00000204842; -. DR Orphanet; 803; Amyotrophic lateral sclerosis. DR Orphanet; 98756; Spinocerebellar ataxia type 2. DR VEuPathDB; HostDB:ENSG00000204842; -. DR eggNOG; KOG2375; Eukaryota. DR GeneTree; ENSGT00940000156812; -. DR InParanoid; Q99700; -. DR OMA; RMQMSAS; -. DR OrthoDB; 2275718at2759; -. DR PAN-GO; Q99700; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q99700; -. DR PathwayCommons; Q99700; -. DR SignaLink; Q99700; -. DR SIGNOR; Q99700; -. DR Agora; ENSG00000204842; -. DR BioGRID-ORCS; 6311; 15 hits in 1159 CRISPR screens. DR CD-CODE; 232F8A39; P-body. DR CD-CODE; DEE660B4; Stress granule. DR CD-CODE; E1879998; Synthetic Condensate 000375. DR ChiTaRS; ATXN2; human. DR GeneWiki; ATXN2; -. DR GenomeRNAi; 6311; -. DR Pharos; Q99700; Tbio. DR PRO; PR:Q99700; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; Q99700; protein. DR Bgee; ENSG00000204842; Expressed in buccal mucosa cell and 197 other cell types or tissues. DR ExpressionAtlas; Q99700; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0010494; C:cytoplasmic stress granule; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:1990904; C:ribonucleoprotein complex; IDA:UniProtKB. DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB. DR GO; GO:0005154; F:epidermal growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0003729; F:mRNA binding; IBA:GO_Central. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0002091; P:negative regulation of receptor internalization; IMP:UniProtKB. DR GO; GO:0033962; P:P-body assembly; IMP:UniProtKB. DR GO; GO:0006417; P:regulation of translation; NAS:UniProtKB. DR GO; GO:0016070; P:RNA metabolic process; NAS:UniProtKB. DR GO; GO:0050658; P:RNA transport; NAS:UniProtKB. DR GO; GO:0034063; P:stress granule assembly; IMP:UniProtKB. DR CDD; cd00600; Sm_like; 1. DR IDEAL; IID00580; -. DR InterPro; IPR045117; ATXN2-like. DR InterPro; IPR010920; LSM_dom_sf. DR InterPro; IPR009604; LsmAD_domain. DR InterPro; IPR009818; PAM2_motif. DR InterPro; IPR047575; Sm. DR InterPro; IPR025852; SM_dom_ATX. DR PANTHER; PTHR12854; ATAXIN 2-RELATED; 1. DR PANTHER; PTHR12854:SF11; ATAXIN-2; 1. DR Pfam; PF06741; LsmAD; 1. DR Pfam; PF07145; PAM2; 1. DR Pfam; PF14438; SM-ATX; 1. DR SMART; SM01272; LsmAD; 1. DR SUPFAM; SSF81995; beta-sandwich domain of Sec23/24; 1. DR SUPFAM; SSF50182; Sm-like ribonucleoproteins; 1. DR PROSITE; PS52002; SM; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis; KW Cytoplasm; Isopeptide bond; Methylation; Neurodegeneration; Parkinsonism; KW Phosphoprotein; Proteomics identification; Reference proteome; KW Spinocerebellar ataxia; Triplet repeat expansion; Ubl conjugation. FT CHAIN 1..1313 FT /note="Ataxin-2" FT /id="PRO_0000064756" FT DOMAIN 267..344 FT /note="Sm" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01346" FT REGION 1..255 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 459..954 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1137..1219 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1..12 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 48..65 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 104..114 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 141..154 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 166..187 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 204..234 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 235..244 FT /note="Gly residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 459..471 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 478..492 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 508..544 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 552..562 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 563..581 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 582..598 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 627..637 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 666..681 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 693..703 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 768..777 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 788..804 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 807..820 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 821..844 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 847..871 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 880..891 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 893..910 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 925..936 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1155..1192 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1206..1219 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 248 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 393 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 466 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 478 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 508 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 554 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 624 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 640 FT /note="Asymmetric dimethylarginine; alternate" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 640 FT /note="Omega-N-methylarginine; alternate" FT /evidence="ECO:0007744|PubMed:24129315" FT MOD_RES 642 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 684 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:23186163" FT MOD_RES 728 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 741 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 772 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 784 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 856 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 857 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 861 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692" FT MOD_RES 865 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692" FT MOD_RES 867 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:O70305" FT MOD_RES 888 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648" FT MOD_RES 889 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT CROSSLNK 893 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1..981 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011574" FT VAR_SEQ 1..265 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057285" FT VAR_SEQ 277..300 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057286" FT VAR_SEQ 980..995 FT /note="PLYPIPMTPMPVNQAK -> YQICPNSGKTSIIRVP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011575" FT VAR_SEQ 982..998 FT /note="YPIPMTPMPVNQAKTYR -> MYYAVEILFNRQSAFFS (in isoform FT 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011576" FT VAR_SEQ 996..1313 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8896557" FT /id="VSP_011577" FT VAR_SEQ 1106..1124 FT /note="ACPKLPYNKETSPSFYFAI -> V (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_057287" FT VAR_SEQ 1106..1123 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011578" FT VAR_SEQ 1124 FT /note="I -> V (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011579" FT VAR_SEQ 1244..1313 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_011582" FT VAR_SEQ 1249..1257 FT /note="AHVQSGMVP -> VIPALANFL (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011580" FT VAR_SEQ 1258..1313 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_011581" FT VARIANT 107 FT /note="L -> V (in dbSNP:rs695871)" FT /evidence="ECO:0000269|PubMed:8896555, FT ECO:0000269|PubMed:8896557" FT /id="VAR_047629" FT VARIANT 248 FT /note="S -> N (in dbSNP:rs7969300)" FT /id="VAR_047630" FT CONFLICT 188 FT /note="Missing (in Ref. 1; AAB19200 and 6; CAA69589)" FT /evidence="ECO:0000305" SQ SEQUENCE 1313 AA; 140283 MW; 40A2883FF9D5D118 CRC64; MRSAAAAPRS PAVATESRRF AAARWPGWRS LQRPARRSGR GGGGAAPGPY PSAAPPPPGP GPPPSRQSSP PSASDCFGSN GNGGGAFRPG SRRLLGLGGP PRPFVVLLLP LASPGAPPAA PTRASPLGAR ASPPRSGVSL ARPAPGCPRP ACEPVYGPLT MSLKPQQQQQ QQQQQQQQQQ QQQQQQQQPP PAAANVRKPG GSGLLASPAA APSPSSSSVS SSSATAPSSV VAATSGGGRP GLGRGRNSNK GLPQSTISFD GIYANMRMVH ILTSVVGSKC EVQVKNGGIY EGVFKTYSPK CDLVLDAAHE KSTESSSGPK REEIMESILF KCSDFVVVQF KDMDSSYAKR DAFTDSAISA KVNGEHKEKD LEPWDAGELT ANEELEALEN DVSNGWDPND MFRYNEENYG VVSTYDSSLS SYTVPLERDN SEEFLKREAR ANQLAEEIES SAQYKARVAL ENDDRSEEEK YTAVQRNSSE REGHSINTRE NKYIPPGQRN REVISWGSGR QNSPRMGQPG SGSMPSRSTS HTSDFNPNSG SDQRVVNGGV PWPSPCPSPS SRPPSRYQSG PNSLPPRAAT PTRPPSRPPS RPSRPPSHPS AHGSPAPVST MPKRMSSEGP PRMSPKAQRH PRNHRVSAGR GSISSGLEFV SHNPPSEAAT PPVARTSPSG GTWSSVVSGV PRLSPKTHRP RSPRQNSIGN TPSGPVLASP QAGIIPTEAV AMPIPAASPT PASPASNRAV TPSSEAKDSR LQDQRQNSPA GNKENIKPNE TSPSFSKAEN KGISPVVSEH RKQIDDLKKF KNDFRLQPSS TSESMDQLLN KNREGEKSRD LIKDKIEPSA KDSFIENSSS NCTSGSSKPN SPSISPSILS NTEHKRGPEV TSQGVQTSSP ACKQEKDDKE EKKDAAEQVR KSTLNPNAKE FNPRSFSQPK PSTTPTSPRP QAQPSPSMVG HQQPTPVYTQ PVCFAPNMMY PVPVSPGVQP LYPIPMTPMP VNQAKTYRAV PNMPQQRQDQ HHQSAMMHPA SAAGPPIAAT PPAYSTQYVA YSPQQFPNQP LVQHVPHYQS QHPHVYSPVI QGNARMMAPP THAQPGLVSS SATQYGAHEQ THAMYACPKL PYNKETSPSF YFAISTGSLA QQYAHPNATL HPHTPHPQPS ATPTGQQQSQ HGGSHPAPSP VQHHQHQAAQ ALHLASPQQQ SAIYHAGLAP TPPSMTPASN TQSPQNSFPA AQQTVFTIHP SHVQPAYTNP PHMAHVPQAH VQSGMVPSHP TAHAPMMLMT TQPPGGPQAA LAQSALQPIP VSTTAHFPYM THPSVQAHHQ QQL // ID DPOG1_HUMAN Reviewed; 1239 AA. AC P54098; Q8NFM2; Q92515; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 28-JAN-2026, entry version 236. DE RecName: Full=DNA polymerase subunit gamma-1; DE EC=2.7.7.7 {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:9558343}; DE AltName: Full=3'-5' exodeoxyribonuclease; DE EC=3.1.11.- {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:9558343}; DE AltName: Full=5'-deoxyribose-phosphate lyase; DE EC=4.2.99.- {ECO:0000269|PubMed:9770471}; DE AltName: Full=Mitochondrial DNA polymerase catalytic subunit; DE AltName: Full=PolG-alpha; GN Name=POLG {ECO:0000303|PubMed:10827171, ECO:0000312|HGNC:HGNC:9179}; GN Synonyms=MDP1, POLG1 {ECO:0000303|PubMed:12707443}, POLGA; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND DOMAIN. RX PubMed=8884268; DOI=10.1006/geno.1996.0490; RA Ropp P.A., Copeland W.C.; RT "Cloning and characterization of the human mitochondrial DNA polymerase, RT DNA polymerase gamma."; RL Genomics 36:449-458(1996). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=9034326; DOI=10.1016/s0378-1119(96)00663-4; RA Lecrenier N.L., van der Bruggen P., Foury F.; RT "Mitochondrial DNA polymerases from yeast to man: a new family of RT polymerases."; RL Gene 185:147-152(1997). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT GLN-GLN-55 INS. RC TISSUE=Brain; RA Watanabe T.K., Shimizu F., Nishino N., Fujiwara T., Kanemoto N., Suzuki M., RA Nakamura Y., Hirai Y., Maekawa H., Takahashi E.; RL Submitted (MAR-1996) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLN-55 INS; GLN-193; RP CYS-546; LYS-662; TRP-1142; GLY-1143; CYS-1146 AND HIS-1236. RG NIEHS SNPs program; RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lymph, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9558343; DOI=10.1021/bi972685u; RA Graves S.W., Johnson A.A., Johnson K.A.; RT "Expression, purification, and initial kinetic characterization of the RT large subunit of the human mitochondrial DNA polymerase."; RL Biochemistry 37:6050-6058(1998). RN [7] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=9770471; DOI=10.1073/pnas.95.21.12244; RA Longley M.J., Prasad R., Srivastava D.K., Wilson S.H., Copeland W.C.; RT "Identification of 5'-deoxyribose phosphate lyase activity in human DNA RT polymerase gamma and its role in mitochondrial base excision repair in RT vitro."; RL Proc. Natl. Acad. Sci. U.S.A. 95:12244-12248(1998). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP ASP-198; ASP-890 AND ASP-1135. RX PubMed=10827171; DOI=10.1074/jbc.m000559200; RA Spelbrink J.N., Toivonen J.M., Hakkaart G.A., Kurkela J.M., Cooper H.M., RA Lehtinen S.K., Lecrenier N., Back J.W., Speijer D., Foury F., Jacobs H.T.; RT "In vivo functional analysis of the human mitochondrial DNA polymerase POLG RT expressed in cultured human cells."; RL J. Biol. Chem. 275:24818-24828(2000). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF GLU-200. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [11] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [12] RP REVIEW, AND DOMAIN. RX PubMed=15189144; DOI=10.1146/annurev.biochem.72.121801.161455; RA Kaguni L.S.; RT "DNA polymerase gamma, the mitochondrial replicase."; RL Annu. Rev. Biochem. 73:293-320(2004). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [14] RP SUBCELLULAR LOCATION, ASSOCIATION WITH MITOCHONDRIAL DNA, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=18063578; DOI=10.1074/jbc.m708444200; RA Bogenhagen D.F., Rousseau D., Burke S.; RT "The layered structure of human mitochondrial DNA nucleoids."; RL J. Biol. Chem. 283:3665-3675(2008). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF ASP-274, CHARACTERIZATION OF RP VARIANT LS HIS-232, CHARACTERIZATION OF VARIANTS PEOB1 ALA-268 AND ARG-304, RP AND CHARACTERIZATION OF VARIANTS GLN-275; LEU-277; ARG-303 AND ARG-305. RX PubMed=26095671; DOI=10.1038/ncomms8303; RA Macao B., Uhler J.P., Siibak T., Zhu X., Shi Y., Sheng W., Olsson M., RA Stewart J.B., Gustafsson C.M., Falkenberg M.; RT "The exonuclease activity of DNA polymerase gamma is required for ligation RT during mitochondrial DNA replication."; RL Nat. Commun. 6:7303-7303(2015). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [17] RP INTERACTION WITH TTC3. RX PubMed=29290964; DOI=10.18632/oncotarget.22476; RA Gong Y., Wang X., Shang X., Xiao S.P., Li W., Shang Y., Dou F.; RT "Tetratricopeptide repeat domain 3 overexpression tends to form aggregates RT and inhibit ubiquitination and degradation of DNA polymerase gamma."; RL Oncotarget 8:106475-106485(2017). RN [18] RP INTERACTION WITH LIG3. RX PubMed=33855352; DOI=10.1093/brain/awab056; RA Bonora E., Chakrabarty S., Kellaris G., Tsutsumi M., Bianco F., RA Bergamini C., Ullah F., Isidori F., Liparulo I., Diquigiovanni C., RA Masin L., Rizzardi N., Cratere M.G., Boschetti E., Papa V., Maresca A., RA Cenacchi G., Casadio R., Martelli P., Matera I., Ceccherini I., Fato R., RA Raiola G., Arrigo S., Signa S., Sementa A.R., Severino M., Striano P., RA Fiorillo C., Goto T., Uchino S., Oyazato Y., Nakamura H., Mishra S.K., RA Yeh Y.S., Kato T., Nozu K., Tanboon J., Morioka I., Nishino I., Toda T., RA Goto Y.I., Ohtake A., Kosaki K., Yamaguchi Y., Nonaka I., Iijima K., RA Mimaki M., Kurahashi H., Raams A., MacInnes A., Alders M., Engelen M., RA Linthorst G., de Koning T., den Dunnen W., Dijkstra G., van Spaendonck K., RA van Gent D.C., Aronica E.M., Picco P., Carelli V., Seri M., Katsanis N., RA Duijkers F.A.M., Taniguchi-Ikeda M., De Giorgio R.; RT "Biallelic variants in LIG3 cause a novel mitochondrial RT neurogastrointestinal encephalomyopathy."; RL Brain 144:1451-1466(2021). RN [19] RP X-RAY CRYSTALLOGRAPHY (3.24 ANGSTROMS) OF 70-1239, FUNCTION, CATALYTIC RP ACTIVITY, SUBUNIT, AND MUTAGENESIS OF 543-VAL--LEU-558; LEU-549; LEU-552 RP AND LYS-553. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [20] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 30-1239 IN COMPLEX WITH MG(2+); RP PRIMER-TEMPLATE; 2',3'-DIDEOXYCYTIDINE 5'-TRIPHOSPHATE AND INHIBITOR RP ZALCITABINE, COFACTOR, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, RP SUBUNIT, MUTAGENESIS OF LYS-498; LYS-499 AND LYS-501, AND DOMAIN. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [21] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS) IN COMPLEX WITH RP 2'-DEOXYCYTIDINE-5'-TRIPHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP ACTIVE SITE, SITE, AND MUTAGENESIS OF ASP-198; GLU-200 AND ARG-853. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [22] RP VARIANTS PEOB1 PRO-3; ARG-304; THR-467 AND CYS-955. RX PubMed=11431686; DOI=10.1038/90034; RA Van Goethem G., Dermaut B., Loefgren A., Martin J.-J., Van Broeckhoven C.; RT "Mutation of POLG is associated with progressive external ophthalmoplegia RT characterized by mtDNA deletions."; RL Nat. Genet. 28:211-212(2001). RN [23] RP VARIANTS PEOA1 ASP-923; HIS-943; CYS-955; SER-957 AND LEU-1176, AND RP VARIANTS PEOB1 ILE-251; LEU-309 AND SER-848. RX PubMed=12210792; DOI=10.1002/ana.10278; RA Lamantea E., Tiranti V., Bordoni A., Toscano A., Bono F., Servidei S., RA Papadimitriou A., Spelbrink H., Silvestri L., Casari G., Comi G.P., RA Zeviani M.; RT "Mutations of mitochondrial DNA polymerase gammaA are a frequent cause of RT autosomal dominant or recessive progressive external ophthalmoplegia."; RL Ann. Neurol. 52:211-219(2002). RN [24] RP CHARACTERIZATION OF VARIANT PEOA1 CYS-955, FUNCTION, AND CATALYTIC RP ACTIVITY. RX PubMed=11897778; DOI=10.1074/jbc.c200100200; RA Ponamarev M.V., Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "Active site mutation in DNA polymerase gamma associated with progressive RT external ophthalmoplegia causes error-prone DNA synthesis."; RL J. Biol. Chem. 277:15225-15228(2002). RN [25] RP VARIANTS PEOB1 TRP-579; LEU-587; THR-889 AND VAL-1076, AND VARIANT RP HIS-1236. RX PubMed=12975295; DOI=10.1001/archneur.60.9.1279; RA Filosto M., Mancuso M., Nishigaki Y., Pancrudo J., Harati Y., Gooch C., RA Mankodi A., Bayne L., Bonilla E., Shanske S., Hirano M., DiMauro S.; RT "Clinical and genetic heterogeneity in progressive external ophthalmoplegia RT due to mutations in polymerase gamma."; RL Arch. Neurol. 60:1279-1284(2003). RN [26] RP VARIANTS MTDPS4B ILE-251; LEU-587 AND SER-864. RX PubMed=12825077; DOI=10.1038/sj.ejhg.5201002; RA Van Goethem G., Schwartz M., Loefgren A., Dermaut B., Van Broeckhoven C., RA Vissing J.; RT "Novel POLG mutations in progressive external ophthalmoplegia mimicking RT mitochondrial neurogastrointestinal encephalomyopathy."; RL Eur. J. Hum. Genet. 11:547-549(2003). RN [27] RP VARIANT PEOB1 SER-848. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [28] RP VARIANTS PEOB1 ILE-251; ALA-268; ARG-312; THR-467; GLN-562; LEU-587; RP PRO-807 AND TYR-932, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=14635118; DOI=10.1002/humu.9203; RA Di Fonzo A., Bordoni A., Crimi M., Sara G., Del Bo R., Bresolin N., RA Comi G.P.; RT "POLG mutations in sporadic mitochondrial disorders with multiple mtDNA RT deletions."; RL Hum. Mutat. 22:498-499(2003). RN [29] RP VARIANTS PEOB1 TRP-227; ILE-251; ARG-312; VAL-431; THR-467; GLN-1047; RP CYS-1096 AND CYS-1104. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [30] RP VARIANT SCAE THR-467. RX PubMed=14694057; DOI=10.1212/01.wnl.0000098997.23471.65; RA Van Goethem G., Mercelis R., Loefgren A., Seneca S., Ceuterick C., RA Martin J.-J., Van Broeckhoven C.; RT "Patient homozygous for a recessive POLG mutation presents with features of RT MERRF."; RL Neurology 61:1811-1813(2003). RN [31] RP VARIANTS SANDO PRO-3; ARG-304; THR-467; TRP-627 AND CYS-955. RX PubMed=12565911; DOI=10.1016/s0960-8966(02)00216-x; RA Van Goethem G., Martin J.-J., Dermaut B., Loefgren A., Wibail A., RA Ververken D., Tack P., Dehaene I., Van Zandijcke M., Moonen M., RA Ceuterick C., De Jonghe P., Van Broeckhoven C.; RT "Recessive POLG mutations presenting with sensory and ataxic neuropathy in RT compound heterozygote patients with progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 13:133-142(2003). RN [32] RP VARIANT MTDPS4A THR-467. RX PubMed=15122711; DOI=10.1002/ana.20079; RA Naviaux R.K., Nguyen K.V.; RT "POLG mutations associated with Alpers' syndrome and mitochondrial DNA RT depletion."; RL Ann. Neurol. 55:706-712(2004). RN [33] RP VARIANTS PEOB1 TRP-227; ILE-251; LEU-309; LEU-587; SER-848; ILE-1106 AND RP LEU-1176. RX PubMed=15349879; DOI=10.1002/ana.20219; RA Lamantea E., Zeviani M.; RT "Sequence analysis of familial PEO shows additional mutations associated RT with the 752C-->T and 3527C-->T changes in the POLG1 gene."; RL Ann. Neurol. 56:454-455(2004). RN [34] RP VARIANT PEOA1 CYS-831. RX PubMed=15534189; DOI=10.1001/archneur.61.11.1777; RA Mancuso M., Filosto M., Oh S.J., DiMauro S.; RT "A novel polymerase gamma mutation in a family with ophthalmoplegia, RT neuropathy, and parkinsonism."; RL Arch. Neurol. 61:1777-1779(2004). RN [35] RP VARIANTS PEOA1 CYS-953 AND CYS-955, AND VARIANTS PEOB1 ASP-468 AND RP THR-1105. RX PubMed=15351195; DOI=10.1016/s0140-6736(04)16983-3; RA Luoma P., Melberg A., Rinne J.O., Kaukonen J.A., Nupponen N.N., RA Chalmers R.M., Oldfors A., Rautakorpi I., Peltonen L., Majamaa K., RA Somer H., Suomalainen A.; RT "Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma RT mutations: clinical and molecular genetic study."; RL Lancet 364:875-882(2004). RN [36] RP VARIANTS SANDO TYR-932 AND ARG-1051. RX PubMed=14745080; DOI=10.1212/wnl.62.2.316; RA Mancuso M., Filosto M., Bellan M., Liguori R., Montagna P., Baruzzi A., RA DiMauro S., Carelli V.; RT "POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, RT ataxia, and deafness."; RL Neurology 62:316-318(2004). RN [37] RP VARIANT PEOB1 THR-467, VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=15477547; DOI=10.1212/01.wnl.0000140494.58732.83; RA Van Goethem G., Luoma P., Rantamaeki M., Al-Memar A., Kaakkola S., RA Hackman P., Krahe R., Loefgren A., Martin J.-J., De Jonghe P., RA Suomalainen A., Udd B., Van Broeckhoven C.; RT "POLG mutations in neurodegenerative disorders with ataxia but no muscle RT involvement."; RL Neurology 63:1251-1257(2004). RN [38] RP VARIANT SANDO SER-748, AND VARIANT GLY-1143. RX PubMed=16080118; DOI=10.1086/444548; RA Hakonen A.H., Heiskanen S., Juvonen V., Lappalainen I., Luoma P.T., RA Rantamaeki M., Van Goethem G., Loefgren A., Hackman P., Paetau A., RA Kaakkola S., Majamaa K., Varilo T., Udd B., Kaeaeriaeinen H., Bindoff L.A., RA Suomalainen A.; RT "Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal RT recessive ataxia with ancient European origin."; RL Am. J. Hum. Genet. 77:430-441(2005). RN [39] RP VARIANTS MTDPS4A SER-748 AND SER-848. RX PubMed=15929042; DOI=10.1002/ana.20498; RA Davidzon G., Mancuso M., Ferraris S., Quinzii C., Hirano M., Peters H.L., RA Kirby D., Thorburn D.R., DiMauro S.; RT "POLG mutations and Alpers syndrome."; RL Ann. Neurol. 57:921-923(2005). RN [40] RP VARIANTS MTDPS4A GLY-232; PRO-244; ILE-251; THR-467; LEU-587; SER-748; RP SER-848 AND PRO-957, AND VARIANT GLY-1143. RX PubMed=15689359; DOI=10.1093/brain/awh410; RA Ferrari G., Lamantea E., Donati A., Filosto M., Briem E., Carrara F., RA Parini R., Simonati A., Santer R., Zeviani M.; RT "Infantile hepatocerebral syndromes associated with mutations in the RT mitochondrial DNA polymerase-gammaA."; RL Brain 128:723-731(2005). RN [41] RP VARIANT PEOB1 THR-467, VARIANT SANDO GLN-627, VARIANT HIS-1236, RP CHARACTERIZATION OF VARIANT PEOB1 THR-467, CHARACTERIZATION OF VARIANT RP SANDO GLN-627, FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15917273; DOI=10.1093/hmg/ddi196; RA Luoma P.T., Luo N., Loescher W.N., Farr C.L., Horvath R., Wanschitz J., RA Kiechl S., Kaguni L.S., Suomalainen A.; RT "Functional defects due to spacer-region mutations of human mitochondrial RT DNA polymerase in a family with an ataxia-myopathy syndrome."; RL Hum. Mol. Genet. 14:1907-1920(2005). RN [42] RP VARIANTS SANDO THR-467; HIS-497 AND SER-748. RX PubMed=15824347; DOI=10.1212/01.wnl.0000156516.77696.5a; RA Winterthun S., Ferrari G., He L., Taylor R.W., Zeviani M., Turnbull D.M., RA Engelsen B.A., Moen G., Bindoff L.A.; RT "Autosomal recessive mitochondrial ataxic syndrome due to mitochondrial RT polymerase gamma mutations."; RL Neurology 64:1204-1208(2005). RN [43] RP VARIANTS PEOB1 ARG-737 AND TRP-853. RX PubMed=16634032; DOI=10.1002/ana.20831; RA Davidzon G., Greene P., Mancuso M., Klos K.J., Ahlskog J.E., Hirano M., RA DiMauro S.; RT "Early-onset familial parkinsonism due to POLG mutations."; RL Ann. Neurol. 59:859-862(2006). RN [44] RP VARIANTS PEOB1 LEU-603; TRP-853; CYS-1146 AND ASN-1184. RX PubMed=16401742; DOI=10.1001/archneur.63.1.107; RA Gonzalez-Vioque E., Blazquez A., Fernandez-Moreira D., Bornstein B., RA Bautista J., Arpa J., Navarro C., Campos Y., Fernandez-Moreno M.A., RA Garesse R., Arenas J., Martin M.A.; RT "Association of novel POLG mutations and multiple mitochondrial DNA RT deletions with variable clinical phenotypes in a Spanish population."; RL Arch. Neurol. 63:107-111(2006). RN [45] RP VARIANTS PEOB1 HIS-308; TRP-574 AND ARG-648, VARIANT SANDO VAL-517, AND RP VARIANTS MTDPS4A ASP-767; HIS-879; SER-885; PRO-914; HIS-1096 AND ASN-1191. RX PubMed=16621917; DOI=10.1093/brain/awl088; RA Horvath R., Hudson G., Ferrari G., Fuetterer N., Ahola S., Lamantea E., RA Prokisch H., Lochmueller H., McFarland R., Ramesh V., Klopstock T., RA Freisinger P., Salvi F., Mayr J.A., Santer R., Tesarova M., Zeman J., RA Udd B., Taylor R.W., Turnbull D., Hanna M., Fialho D., Suomalainen A., RA Zeviani M., Chinnery P.F.; RT "Phenotypic spectrum associated with mutations of the mitochondrial RT polymerase gamma gene."; RL Brain 129:1674-1684(2006). RN [46] RP VARIANTS PEOB1 ARG-304; ASP-380 AND THR-467, VARIANT SANDO SER-748, VARIANT RP MTDPS4A PRO-914, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [47] RP ERRATUM OF PUBMED:16639411. RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RL Eur. J. Hum. Genet. 15:607-607(2006). RN [48] RP VARIANTS SANDO ARG-648 AND CYS-807. RX PubMed=16919951; DOI=10.1016/j.nmd.2006.05.016; RA Gago M.F., Rosas M.J., Guimaraes J., Ferreira M., Vilarinho L., Castro L., RA Carpenter S.; RT "SANDO: two novel mutations in POLG1 gene."; RL Neuromuscul. Disord. 16:507-509(2006). RN [49] RP VARIANT PEOA1 ASN-511, AND VARIANT PHE-463. RX PubMed=17420318; DOI=10.1001/archneur.64.4.553; RA Hudson G., Schaefer A.M., Taylor R.W., Tiangyou W., Gibson A., Venables G., RA Griffiths P., Burn D.J., Turnbull D.M., Chinnery P.F.; RT "Mutation of the linker region of the polymerase gamma-1 (POLG1) gene RT associated with progressive external ophthalmoplegia and Parkinsonism."; RL Arch. Neurol. 64:553-557(2007). RN [50] RP VARIANT PEOA1 CYS-831. RX PubMed=17846414; DOI=10.1212/01.wnl.0000276955.23735.eb; RA Luoma P.T., Eerola J., Ahola S., Hakonen A.H., Hellstroem O., RA Kivistoe K.T., Tienari P.J., Suomalainen A.; RT "Mitochondrial DNA polymerase gamma variants in idiopathic sporadic RT Parkinson disease."; RL Neurology 69:1152-1159(2007). RN [51] RP VARIANT PEOA1 HIS-1186. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [52] RP VARIANTS LS HIS-232 AND SER-848, VARIANTS MTDPS4A ILE-251; THR-467; RP LEU-587; SER-748; CYS-831; SER-848; PRO-914; TYR-1110; ARG-1134 AND RP LYS-1136, AND VARIANTS GLY-1143 AND HIS-1236. RX PubMed=18828154; DOI=10.1002/humu.20852; RA Taanman J.-W., Rahman S., Pagnamenta A.T., Morris A.A.M., RA Bitner-Glindzicz M., Wolf N.I., Leonard J.V., Clayton P.T., RA Schapira A.H.V.; RT "Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA RT depletion."; RL Hum. Mutat. 30:248-254(2009). RN [53] RP VARIANTS MTDPS4B TRP-227 AND SER-848. RX PubMed=19307547; DOI=10.1212/01.wnl.0000345002.47396.e1; RA Giordano C., Powell H., Leopizzi M., de Curtis M., Travaglini C., RA Sebastiani M., Gallo P., Taylor R.W., d'Amati G.; RT "Fatal congenital myopathy and gastrointestinal pseudo-obstruction due to RT POLG1 mutations."; RL Neurology 72:1103-1105(2009). RN [54] RP VARIANTS SCAE THR-467 AND SER-748, AND VARIANTS MTDPS4A ARG-303; THR-467 RP AND SER-848. RX PubMed=20400524; DOI=10.1093/brain/awq067; RA Tzoulis C., Neckelmann G., Moerk S.J., Engelsen B.E., Viscomi C., Moen G., RA Ersland L., Zeviani M., Bindoff L.A.; RT "Localized cerebral energy failure in DNA polymerase gamma-associated RT encephalopathy syndromes."; RL Brain 133:1428-1437(2010). RN [55] RP VARIANTS PEOB1 LEU-277 AND CYS-943. RX PubMed=21301859; DOI=10.1007/s00415-011-5936-x; RA Sato K., Yabe I., Yaguchi H., Nakano F., Kunieda Y., Saitoh S., Sasaki H.; RT "Genetic analysis of two Japanese families with progressive external RT ophthalmoplegia and parkinsonism."; RL J. Neurol. 258:1327-1332(2011). RN [56] RP VARIANTS MTDPS4A ARG-305; THR-467; SER-748; SER-848; CYS-852 AND ARG-966. RX PubMed=22000311; DOI=10.1016/j.pediatrneurol.2011.07.008; RA Hunter M.F., Peters H., Salemi R., Thorburn D., Mackay M.T.; RT "Alpers syndrome with mutations in POLG: clinical and investigative RT features."; RL Pediatr. Neurol. 45:311-318(2011). RN [57] RP VARIANT MTDPS4A CYS-1096. RX PubMed=25129007; DOI=10.1007/s13312-014-0475-z; RA Bijarnia-Mahay S., Mohan N., Goyal D., Verma I.C.; RT "Mitochondrial DNA depletion syndrome causing liver failure."; RL Indian Pediatr. 51:666-668(2014). RN [58] RP INVOLVEMENT IN SCAE, AND VARIANTS SCAE THR-467; HIS-497 AND SER-748. RX PubMed=26942291; DOI=10.1016/j.ajhg.2016.01.009; RA Sandford E., Bird T.D., Li J.Z., Burmeister M.; RT "PRICKLE2 mutations might not be involved in epilepsy."; RL Am. J. Hum. Genet. 98:588-589(2016). RN [59] RP VARIANTS GLN-275 AND SER-848. RX PubMed=30552426; DOI=10.1038/s41431-018-0299-8; RA Papuc S.M., Abela L., Steindl K., Begemann A., Simmons T.L., Schmitt B., RA Zweier M., Oneda B., Socher E., Crowther L.M., Wohlrab G., Gogoll L., RA Poms M., Seiler M., Papik M., Baldinger R., Baumer A., Asadollahi R., RA Kroell-Seger J., Schmid R., Iff T., Schmitt-Mechelke T., Otten K., RA Hackenberg A., Addor M.C., Klein A., Azzarello-Burri S., Sticht H., RA Joset P., Plecko B., Rauch A.; RT "The role of recessive inheritance in early-onset epileptic RT encephalopathies: a combined whole-exome sequencing and copy number RT study."; RL Eur. J. Hum. Genet. 27:408-421(2019). CC -!- FUNCTION: Catalytic subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Replicates both heavy and CC light strands of the circular mtDNA genome using a single-stranded DNA CC template, RNA primers and the four deoxyribonucleoside triphosphates as CC substrates (PubMed:11477093, PubMed:11897778, PubMed:15917273, CC PubMed:19837034, PubMed:9558343). Has 5' -> 3' polymerase activity. CC Functionally interacts with TWNK and SSBP1 at the replication fork to CC form a highly processive replisome, where TWNK unwinds the double- CC stranded DNA template prior to replication and SSBP1 covers the CC parental heavy strand to enable continuous replication of the entire CC mitochondrial genome. A single nucleotide incorporation cycle includes CC binding of the incoming nucleotide at the insertion site, a CC phosphodiester bond formation reaction that extends the 3'-end of the CC primer DNA, and translocation of the primer terminus to the post- CC insertion site. After completing replication of a mtDNA strand, CC mediates 3' -> 5' exonucleolytic degradation at the nick to enable CC proper ligation (PubMed:11477093, PubMed:11897778, PubMed:15167897, CC PubMed:15917273, PubMed:19837034, PubMed:26095671, PubMed:9558343). CC Highly accurate due to high nucleotide selectivity and 3' -> 5' CC exonucleolytic proofreading. Proficiently corrects base substitutions, CC single-base additions and deletions in non-repetitive sequences and CC short repeats, but displays lower proofreading activity when CC replicating longer homopolymeric stretches. Exerts exonuclease activity CC toward single-stranded DNA and double-stranded DNA containing 3'- CC terminal mispairs. When a misincorporation occurs, transitions from CC replication to a pro-nucleolytic editing mode and removes the CC missincorporated nucleoside in the exonuclease active site. Proceeds CC via an SN2 nucleolytic mechanism in which Asp-198 catalyzes CC phosphodiester bond hydrolysis and Glu-200 stabilizes the leaving CC group. As a result the primer strand becomes one nucleotide shorter and CC is positioned in the post-insertion site, ready to resume DNA synthesis CC (PubMed:10827171, PubMed:11477094, PubMed:11504725, PubMed:37202477). CC Exerts 5'-deoxyribose phosphate (dRP) lyase activity and mediates CC repair-associated mtDNA synthesis (gap filling) in base-excision repair CC pathway. Catalyzes the release of the 5'-terminal 2-deoxyribose-5- CC phosphate sugar moiety from incised apurinic/apyrimidinic (AP) sites to CC produce a substrate for DNA ligase. The dRP lyase reaction does not CC require divalent metal ions and likely proceeds via a Schiff base CC intermediate in a beta-elimination reaction mechanism (PubMed:9770471). CC {ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343, ECO:0000269|PubMed:9770471}. CC -!- CATALYTIC ACTIVITY: CC Reaction=DNA(n) + a 2'-deoxyribonucleoside 5'-triphosphate = DNA(n+1) + CC diphosphate; Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, Rhea:RHEA- CC COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:173112; CC EC=2.7.7.7; Evidence={ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:11477093, ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:26095671, ECO:0000269|PubMed:37202477, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22509; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:37202477, ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 3'-end 2'-deoxyribonucleotidyl-deoxyribonucleotide-DNA + H2O CC = a 3'-end 2'-deoxyribonucleotide-DNA + a 2'-deoxyribonucleoside 5'- CC phosphate + H(+); Xref=Rhea:RHEA:77911, Rhea:RHEA-COMP:13863, CC Rhea:RHEA-COMP:19009, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:65317, ChEBI:CHEBI:138148, ChEBI:CHEBI:228185; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:77912; CC Evidence={ECO:0000269|PubMed:10827171, ECO:0000269|PubMed:11477094, CC ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:26095671, CC ECO:0000269|PubMed:9558343}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end 2'-deoxyribose-2'-deoxyribonucleotide-DNA = (2E,4S)- CC 4-hydroxypenten-2-al-5-phosphate + a 5'-end 5'-phospho-2'- CC deoxyribonucleoside-DNA + H(+); Xref=Rhea:RHEA:76255, Rhea:RHEA- CC COMP:13180, Rhea:RHEA-COMP:18657, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:136412, ChEBI:CHEBI:195194, ChEBI:CHEBI:195195; CC Evidence={ECO:0000269|PubMed:9770471}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76256; CC Evidence={ECO:0000269|PubMed:9770471}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:26056153}; CC -!- ACTIVITY REGULATION: Inhibited by dideoxynucleotides such as antiviral CC agent zalcitabine. {ECO:0000269|PubMed:26056153}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.011 uM for dTTP (POLG polymerase activity at matched G:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=0.015 uM for dTTP (POLG:POLG2 polymerase activity at matched G:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=7.6 uM for dTTP (POLG:POLG2 polymerase activity at mismatched A:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=10 uM for dTTP (POLG polymerase activity at mismatched T:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=5.5 uM for dTTP (POLG:POLG2 polymerase activity at mismatched T:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=13 uM for dTTP (POLG polymerase activity at mismatched G:G primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched G:G CC primer-template) {ECO:0000269|PubMed:11504725}; CC KM=55 uM for dTTP (POLG polymerase activity at mismatched C:C primer- CC template) {ECO:0000269|PubMed:11504725}; CC KM=11 uM for dTTP (POLG:POLG2 polymerase activity at mismatched C:C CC primer-template) {ECO:0000269|PubMed:11504725}; CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2) (PubMed:11477093, PubMed:11477094, CC PubMed:15167897, PubMed:19837034, PubMed:26056153, PubMed:37202477). CC Interacts with TTC3 (PubMed:29290964). Interacts with LIG3 CC (PubMed:33855352). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:19837034, ECO:0000269|PubMed:26056153, CC ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC P54098; Q9UHN1: POLG2; NbExp=15; IntAct=EBI-852624, EBI-852642; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:10827171, CC ECO:0000269|PubMed:18063578}. Mitochondrion matrix, mitochondrion CC nucleoid {ECO:0000269|PubMed:18063578}. CC -!- DOMAIN: The polymerase domain encompasses three conserved active site CC motifs: Pol A (residues 887-896), Pol B (residues 943-958) and Pol C CC (residues 1134-1141). Binds the incoming dNTPs and undergoes an open to CC close coformation change to catalyze the formation of phosphodiester CC bond. {ECO:0000269|PubMed:26056153, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The 3' -> 5' exonuclease domain comprises three conserved CC active site motifs: Exo I (residues 196-200), Exo II (residues 267-275) CC and Exo III (residues 395-403). Proofreads the newly synthesized DNA CC strand. {ECO:0000269|PubMed:37202477, ECO:0000303|PubMed:15189144, CC ECO:0000303|PubMed:8884268}. CC -!- DOMAIN: The trigger loop contracts to enable correctly matched primer- CC template pair entry into the polymerase domain and extends to preclude CC the mismatched one. {ECO:0000269|PubMed:37202477}. CC -!- DOMAIN: The accessory determinant domain (AID) interacts with POLG2 CC proximal monomer. {ECO:0000269|PubMed:26056153}. CC -!- POLYMORPHISM: The poly-Gln region seems to be polymorphic. CC {ECO:0000269|Ref.3, ECO:0000269|Ref.4}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 1 (PEOA1) [MIM:157640]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11897778, CC ECO:0000269|PubMed:12210792, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15534189, ECO:0000269|PubMed:17420318, CC ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18575922}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal recessive, 1 (PEOB1) [MIM:258450]: A severe form CC of progressive external ophthalmoplegia, a disorder characterized by CC progressive weakness of ocular muscles and levator muscle of the upper CC eyelid. It is clinically more heterogeneous than the autosomal dominant CC forms. {ECO:0000269|PubMed:11431686, ECO:0000269|PubMed:12210792, CC ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12872260, CC ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, CC ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15351195, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15917273, CC ECO:0000269|PubMed:16401742, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16634032, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:21301859, ECO:0000269|PubMed:26095671}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Sensory ataxic neuropathy dysarthria and ophthalmoparesis CC (SANDO) [MIM:607459]: A systemic disorder resulting from mitochondrial CC dysfunction associated with mitochondrial depletion in skeletal muscle CC and peripheral nerve tissue. The clinical triad of symptoms consists of CC sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, CC the phenotype varies widely, even within the same family, and can also CC include myopathy, seizures, and hearing loss. CC {ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:14745080, CC ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15824347, CC ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16080118, CC ECO:0000269|PubMed:16621917, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:16919951}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4A (MTDPS4A) CC [MIM:203700]: An autosomal recessive hepatocerebral syndrome due to CC mitochondrial dysfunction. The typical course of the disease includes CC severe developmental delay, intractable seizures, liver failure, and CC death in childhood. Refractory seizures, cortical blindness, CC progressive liver dysfunction, and acute liver failure after exposure CC to valproic acid are considered diagnostic features. The CC neuropathological hallmarks are neuronal loss, spongiform degeneration, CC and astrocytosis of the visual cortex. Liver biopsy results show CC steatosis, often progressing to cirrhosis. CC {ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15689359, CC ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:16621917, CC ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:20400524, ECO:0000269|PubMed:22000311, CC ECO:0000269|PubMed:25129007}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 4B (MTDPS4B) CC [MIM:613662]: An autosomal recessive progressive multisystem disorder CC due to mitochondrial dysfunction. It is clinically characterized by CC chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, CC progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, CC and muscle weakness. {ECO:0000269|PubMed:12825077, CC ECO:0000269|PubMed:19307547}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Leigh syndrome (LS) [MIM:256000]: An early-onset progressive CC neurodegenerative disorder characterized by the presence of focal, CC bilateral lesions in one or more areas of the central nervous system CC including the brainstem, thalamus, basal ganglia, cerebellum and spinal CC cord. Clinical features depend on which areas of the central nervous CC system are involved and include subacute onset of psychomotor CC retardation, hypotonia, ataxia, weakness, vision loss, eye movement CC abnormalities, seizures, and dysphagia. {ECO:0000269|PubMed:18828154, CC ECO:0000269|PubMed:26095671}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Spinocerebellar ataxia with epilepsy (SCAE) [MIM:607459]: An CC autosomal recessive syndrome characterized by headaches and/or seizures CC manifesting in childhood or adolescence, cerebellar and sensory ataxia, CC dysarthria, and myoclonus manifesting in early adulthood. CC Neuropathological findings include spinocerebellar degeneration CC associated with cortical neuronal degeneration in advanced cases. CC {ECO:0000269|PubMed:14694057, ECO:0000269|PubMed:20400524, CC ECO:0000269|PubMed:26942291}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the DNA polymerase type-A family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U60325; AAC50712.1; -; mRNA. DR EMBL; X98093; CAA66719.1; -; mRNA. DR EMBL; D84103; BAA12223.1; -; mRNA. DR EMBL; AF497906; AAM77583.1; -; Genomic_DNA. DR EMBL; BC042571; AAH42571.1; -; mRNA. DR EMBL; BC050559; AAH50559.1; -; mRNA. DR CCDS; CCDS10350.1; -. DR PIR; G02750; G02750. DR RefSeq; NP_001119603.1; NM_001126131.2. DR RefSeq; NP_002684.1; NM_002693.3. DR PDB; 3IKM; X-ray; 3.24 A; A/D=70-1239. DR PDB; 4ZTU; X-ray; 3.30 A; A=30-1239. DR PDB; 4ZTZ; X-ray; 3.44 A; A=30-1239. DR PDB; 5C51; X-ray; 3.43 A; A=25-1239. DR PDB; 5C52; X-ray; 3.64 A; A=25-1239. DR PDB; 5C53; X-ray; 3.57 A; A=25-1239. DR PDB; 8D33; EM; 2.46 A; A=1-1239. DR PDB; 8D37; EM; 2.65 A; A=1-1239. DR PDB; 8D3R; EM; 3.04 A; A=1-1239. DR PDB; 8D42; EM; 2.91 A; A=1-1239. DR PDB; 8G5I; EM; 2.75 A; A=1-1239. DR PDB; 8G5J; EM; 2.63 A; A=1-1239. DR PDB; 8G5K; EM; 2.90 A; A=1-1239. DR PDB; 8G5L; EM; 3.00 A; A=1-1239. DR PDB; 8G5M; EM; 2.58 A; A=1-1239. DR PDB; 8G5N; EM; 2.73 A; A=1-1239. DR PDB; 8G5O; EM; 2.61 A; A=1-1239. DR PDB; 8G5P; EM; 2.78 A; A=1-1239. DR PDB; 8T7E; EM; 3.08 A; A=1-1239. DR PDB; 8UDK; X-ray; 3.43 A; A=1-1239. DR PDB; 8UDL; EM; 2.37 A; A=1-1239. DR PDB; 8V54; EM; 4.10 A; A=26-1239. DR PDB; 8V55; EM; 4.20 A; A=26-1239. DR PDB; 8V5D; EM; 3.00 A; A=26-1239. DR PDB; 8V5R; EM; 3.00 A; A=26-1239. DR PDB; 9GGB; EM; 2.63 A; A=26-1239. DR PDB; 9GGC; EM; 2.39 A; A=26-1239. DR PDB; 9GGD; EM; 2.67 A; A=26-1239. DR PDB; 9GGE; EM; 2.69 A; A=26-1239. DR PDB; 9GGF; EM; 2.65 A; A=26-1239. DR PDB; 9IC1; EM; 2.73 A; A=26-1239. DR PDB; 9IC3; EM; 2.96 A; A=26-1239. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5D; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IC1; -. DR PDBsum; 9IC3; -. DR AlphaFoldDB; P54098; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42982; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52824; -. DR EMDB; EMD-52828; -. DR SMR; P54098; -. DR BioGRID; 111424; 116. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; P54098; 1006. DR IntAct; P54098; 64. DR MINT; P54098; -. DR STRING; 9606.ENSP00000399851; -. DR BindingDB; P54098; -. DR ChEMBL; CHEMBL2732; -. DR DrugBank; DB12151; Brincidofovir. DR DrugCentral; P54098; -. DR GlyGen; P54098; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P54098; -. DR PhosphoSitePlus; P54098; -. DR SwissPalm; P54098; -. DR BioMuta; POLG; -. DR DMDM; 1706507; -. DR jPOST; P54098; -. DR MassIVE; P54098; -. DR PaxDb; 9606-ENSP00000268124; -. DR PeptideAtlas; P54098; -. DR ProteomicsDB; 56642; -. DR Pumba; P54098; -. DR Antibodypedia; 28558; 222 antibodies from 35 providers. DR DNASU; 5428; -. DR Ensembl; ENST00000268124.11; ENSP00000268124.5; ENSG00000140521.18. DR Ensembl; ENST00000442287.6; ENSP00000399851.2; ENSG00000140521.18. DR Ensembl; ENST00000636937.2; ENSP00000516154.1; ENSG00000140521.18. DR GeneID; 5428; -. DR KEGG; hsa:5428; -. DR MANE-Select; ENST00000268124.11; ENSP00000268124.5; NM_002693.3; NP_002684.1. DR UCSC; uc002bnr.5; human. DR AGR; HGNC:9179; -. DR ClinPGx; PA33500; -. DR CTD; 5428; -. DR DisGeNET; 5428; -. DR GeneCards; POLG; -. DR GeneReviews; POLG; -. DR HGNC; HGNC:9179; POLG. DR HPA; ENSG00000140521; Low tissue specificity. DR MalaCards; POLG; -. DR MIM; 157640; phenotype. DR MIM; 174763; gene. DR MIM; 203700; phenotype. DR MIM; 256000; phenotype. DR MIM; 258450; phenotype. DR MIM; 607459; phenotype. DR MIM; 613662; phenotype. DR OpenTargets; ENSG00000140521; -. DR Orphanet; 726; Alpers-Huttenlocher syndrome. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 254886; Autosomal recessive progressive external ophthalmoplegia. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR Orphanet; 402082; Progressive myoclonic epilepsy type 5. DR Orphanet; 94125; Recessive mitochondrial ataxia syndrome. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR Orphanet; 254881; Spinocerebellar ataxia with epilepsy. DR VEuPathDB; HostDB:ENSG00000140521; -. DR eggNOG; KOG3657; Eukaryota. DR GeneTree; ENSGT00390000000453; -. DR HOGENOM; CLU_001524_2_2_1; -. DR InParanoid; P54098; -. DR OMA; AMHITNL; -. DR OrthoDB; 5588663at2759; -. DR PAN-GO; P54098; 4 GO annotations based on evolutionary models. DR PhylomeDB; P54098; -. DR PathwayCommons; P54098; -. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; P54098; -. DR SIGNOR; P54098; -. DR Agora; ENSG00000140521; -. DR BioGRID-ORCS; 5428; 224 hits in 1160 CRISPR screens. DR ChiTaRS; POLG; human. DR GeneWiki; POLG; -. DR GenomeRNAi; 5428; -. DR Pharos; P54098; Tchem. DR PRO; PR:P54098; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; P54098; protein. DR Bgee; ENSG00000140521; Expressed in granulocyte and 212 other cell types or tissues. DR ExpressionAtlas; P54098; baseline and differential. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IDA:MGI. DR GO; GO:0008408; F:3'-5' exonuclease activity; IDA:FlyBase. DR GO; GO:0051575; F:5'-deoxyribose-5-phosphate lyase activity; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IDA:UniProtKB. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0008310; F:single-stranded DNA 3'-5' DNA exonuclease activity; IDA:UniProtKB. DR GO; GO:0006284; P:base-excision repair; IDA:UniProtKB. DR GO; GO:0006287; P:base-excision repair, gap-filling; IDA:MGI. DR GO; GO:0006259; P:DNA metabolic process; TAS:ProtInc. DR GO; GO:0045004; P:DNA replication proofreading; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR CDD; cd08641; DNA_pol_gammaA; 1. DR FunFam; 1.10.150.20:FF:000024; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 1.20.5.3960:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000001; DNA polymerase gamma, catalytic subunit; 1. DR FunFam; 3.30.420.390:FF:000002; DNA polymerase gamma, catalytic subunit; 1. DR Gene3D; 1.20.5.3960; -; 1. DR Gene3D; 3.30.420.390; -; 2. DR Gene3D; 3.30.70.370; -; 1. DR Gene3D; 1.10.150.20; 5' to 3' exonuclease, C-terminal subdomain; 1. DR InterPro; IPR019760; DNA-dir_DNA_pol_A_CS. DR InterPro; IPR002297; DNA-dir_DNA_pol_A_mt. DR InterPro; IPR001098; DNA-dir_DNA_pol_A_palm_dom. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR041336; DNApol_Exo. DR InterPro; IPR047580; POLG_palm_dom. DR InterPro; IPR012337; RNaseH-like_sf. DR PANTHER; PTHR10267; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR PANTHER; PTHR10267:SF0; DNA POLYMERASE SUBUNIT GAMMA-1; 1. DR Pfam; PF18136; DNApol_Exo; 1. DR PIRSF; PIRSF000797; DNA_pol_mt; 1. DR PRINTS; PR00867; DNAPOLG. DR SMART; SM00482; POLAc; 1. DR SUPFAM; SSF56672; DNA/RNA polymerases; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR PROSITE; PS00447; DNA_POLYMERASE_A; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; KW DNA-directed DNA polymerase; Epilepsy; Hydrolase; Leigh syndrome; Lyase; KW Magnesium; Mitochondrion; Mitochondrion nucleoid; Neurodegeneration; KW Neuropathy; Nucleotidyltransferase; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transferase. FT CHAIN 1..1239 FT /note="DNA polymerase subunit gamma-1" FT /id="PRO_0000101270" FT REGION 1..68 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 43..55 FT /note="Does not contribute to polymerase and exonuclease FT enzymatic activities" FT /evidence="ECO:0000269|PubMed:10827171" FT REGION 318..340 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 506..531 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 510..571 FT /note="Accessory-interacting determinant" FT /evidence="ECO:0000269|PubMed:26056153" FT REGION 858..864 FT /note="Trigger loop" FT /evidence="ECO:0000269|PubMed:37202477" FT MOTIF 196..200 FT /note="Exo I" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 267..275 FT /note="Exo II" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 395..403 FT /note="Exo III" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 887..896 FT /note="Pol A" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 943..958 FT /note="Pol B" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT MOTIF 1134..1141 FT /note="Pol C" FT /evidence="ECO:0000303|PubMed:15189144, FT ECO:0000303|PubMed:8884268" FT COMPBIAS 9..36 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 44..60 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 198 FT /note="Exonuclease activity" FT /evidence="ECO:0000269|PubMed:37202477" FT BINDING 306 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 579 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 593 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 754 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 763 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 768 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 806 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 849 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 863 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 869 FT /ligand="RNA" FT /ligand_id="ChEBI:CHEBI:33697" FT /ligand_label="primer" FT /evidence="ECO:0000305|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 890 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 891 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 891 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 893 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 895 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 943 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 947 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 951 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1094 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1095 FT /ligand="DNA" FT /ligand_id="ChEBI:CHEBI:16991" FT /ligand_label="template strand" FT /evidence="ECO:0000269|PubMed:37202477, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="a 2'-deoxyribonucleoside 5'-triphosphate" FT /ligand_id="ChEBI:CHEBI:61560" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0000269|PubMed:37202477, ECO:0007744|PDB:4ZTZ, FT ECO:0007744|PDB:8D37" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT BINDING 1135 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /ligand_note="catalytic" FT /evidence="ECO:0000269|PubMed:26056153, FT ECO:0007744|PDB:4ZTZ" FT SITE 853 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT SITE 1102 FT /note="Critical for replication fidelity and mismatch FT recognition" FT /evidence="ECO:0000269|PubMed:37202477" FT VARIANT 3 FT /note="R -> P (in PEOB1 and SANDO; dbSNP:rs121918045)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911" FT /id="VAR_012153" FT VARIANT 18 FT /note="P -> S (in dbSNP:rs3087373)" FT /id="VAR_014904" FT VARIANT 55 FT /note="Q -> QQ" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019265" FT VARIANT 55 FT /note="Q -> QQQ" FT /evidence="ECO:0000269|Ref.3" FT /id="VAR_019266" FT VARIANT 193 FT /note="R -> Q (in dbSNP:rs3176162)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_019267" FT VARIANT 227 FT /note="R -> W (in PEOB1 and MTDPS4B; dbSNP:rs121918056)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:19307547" FT /id="VAR_023663" FT VARIANT 232 FT /note="R -> G (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058870" FT VARIANT 232 FT /note="R -> H (in LS; displays markedly increased FT exonuclease activity and reduced polymerization activity; FT produces ligatable 5'-ends; dbSNP:rs113994093)" FT /evidence="ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058871" FT VARIANT 244 FT /note="L -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058872" FT VARIANT 251 FT /note="T -> I (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994094)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12707443, ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:18828154" FT /id="VAR_023664" FT VARIANT 268 FT /note="G -> A (in PEOB1; sporadic case; displays mildly FT reduced exonuclease activity; does not affect the FT polymerization activity or 5'-end ligation; FT dbSNP:rs61752784)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:26095671" FT /id="VAR_058873" FT VARIANT 275 FT /note="R -> Q (found in a patient with epileptic FT encephalopathy, developmental delay and moderate FT intellectual disability; uncertain significance; displays FT mildly reduced exonuclease activity; reduced polymerization FT activity; reduced DNA-binding affinity; does not affect 5'- FT end ligation; dbSNP:rs1555453950)" FT /evidence="ECO:0000269|PubMed:26095671, FT ECO:0000269|PubMed:30552426" FT /id="VAR_088657" FT VARIANT 277 FT /note="H -> L (in PEOB1; uncertain significance; does not FT affect exonuclease activity; does not affect polymerization FT activity; does not affect 5'-end ligation; FT dbSNP:rs138929605)" FT /evidence="ECO:0000269|PubMed:21301859, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088658" FT VARIANT 303 FT /note="G -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs749799663)" FT /evidence="ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088659" FT VARIANT 304 FT /note="L -> R (in PEOB1 and SANDO; results in loss of FT exonuclease activity and formation of an unligatable 5'- FT flap; displays low polymerization activity and reduced DNA- FT binding affinity; dbSNP:rs121918044)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:26095671" FT /id="VAR_012154" FT VARIANT 304 FT /note="L -> SANDO (in PEOB1)" FT /id="VAR_058874" FT VARIANT 305 FT /note="S -> R (in MTDPS4A; likely pathogenic; results in FT loss of exonuclease activity and formation of an FT unligatable 5'-flap; displays low polymerization activity FT and reduced DNA-binding affinity; dbSNP:rs769410130)" FT /evidence="ECO:0000269|PubMed:22000311, FT ECO:0000269|PubMed:26095671" FT /id="VAR_088660" FT VARIANT 308 FT /note="Q -> H (in PEOB1; sporadic case; dbSNP:rs745539599)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058875" FT VARIANT 309 FT /note="R -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023665" FT VARIANT 312 FT /note="W -> R (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118" FT /id="VAR_023666" FT VARIANT 324 FT /note="P -> S (in dbSNP:rs2307437)" FT /id="VAR_014905" FT VARIANT 380 FT /note="G -> D (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16639411" FT /id="VAR_058876" FT VARIANT 431 FT /note="G -> V (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023667" FT VARIANT 463 FT /note="L -> F (in dbSNP:rs150828914)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058877" FT VARIANT 467 FT /note="A -> T (in PEOB1, SANDO, SCAE and MTDPS4A; FT pathogenic; results in clearly decreased activity, DNA FT binding and processivity of the polymerase; FT dbSNP:rs113994095)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:14694057, FT ECO:0000269|PubMed:15122711, ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15689359, ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:15917273, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_012155" FT VARIANT 468 FT /note="N -> D (in PEOB1; dbSNP:rs145843073)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023668" FT VARIANT 497 FT /note="Q -> H (in SANDO and SCAE; dbSNP:rs121918052)" FT /evidence="ECO:0000269|PubMed:15824347, FT ECO:0000269|PubMed:26942291" FT /id="VAR_023669" FT VARIANT 511 FT /note="S -> N (in PEOA1; dbSNP:rs121918055)" FT /evidence="ECO:0000269|PubMed:17420318" FT /id="VAR_058878" FT VARIANT 517 FT /note="G -> V (in SANDO; dbSNP:rs61752783)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058879" FT VARIANT 546 FT /note="R -> C (in dbSNP:rs2307447)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014906" FT VARIANT 562 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs781168350)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058880" FT VARIANT 574 FT /note="R -> W (in PEOB1; sporadic case; dbSNP:rs774474723)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058881" FT VARIANT 579 FT /note="R -> W (in PEOB1; dbSNP:rs556925652)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023670" FT VARIANT 587 FT /note="P -> L (in PEOB1, MTDPS4A and MTDPS4B; FT dbSNP:rs113994096)" FT /evidence="ECO:0000269|PubMed:12825077, FT ECO:0000269|PubMed:12975295, ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15349879, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:18828154" FT /id="VAR_023671" FT VARIANT 603 FT /note="M -> L (in PEOB1)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058882" FT VARIANT 627 FT /note="R -> Q (in SANDO; shows DNA binding affinity and FT processivities similar to the controls; dbSNP:rs375305567)" FT /evidence="ECO:0000269|PubMed:15917273" FT /id="VAR_058883" FT VARIANT 627 FT /note="R -> W (in SANDO; sporadic case; dbSNP:rs121918046)" FT /evidence="ECO:0000269|PubMed:12565911" FT /id="VAR_023672" FT VARIANT 648 FT /note="P -> R (in PEOB1; sporadic case; also in SANDO; FT dbSNP:rs796052906)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16919951" FT /id="VAR_058884" FT VARIANT 662 FT /note="E -> K (in dbSNP:rs2307450)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014907" FT VARIANT 737 FT /note="G -> R (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918054)" FT /evidence="ECO:0000269|PubMed:16634032" FT /id="VAR_058885" FT VARIANT 748 FT /note="W -> S (in SANDO, SCAE and MTDPS4A; pathogenic; FT dbSNP:rs113994097)" FT /evidence="ECO:0000269|PubMed:15477547, FT ECO:0000269|PubMed:15824347, ECO:0000269|PubMed:15929042, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:26942291" FT /id="VAR_023673" FT VARIANT 767 FT /note="A -> D (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058886" FT VARIANT 807 FT /note="R -> C (in SANDO; dbSNP:rs769827124)" FT /evidence="ECO:0000269|PubMed:16919951" FT /id="VAR_058887" FT VARIANT 807 FT /note="R -> P (in PEOB1; sporadic case)" FT /evidence="ECO:0000269|PubMed:14635118" FT /id="VAR_058888" FT VARIANT 831 FT /note="Y -> C (in PEOA1 and MTDPS4A; uncertain FT significance; dbSNP:rs41549716)" FT /evidence="ECO:0000269|PubMed:15534189, FT ECO:0000269|PubMed:17846414, ECO:0000269|PubMed:18828154" FT /id="VAR_023674" FT VARIANT 848 FT /note="G -> S (in PEOB1, MTDPS4A, MTDPS4B and LS; also FT found in a patient with epileptic encephalopathy, FT developmental delay and moderate intellectual disability; FT dbSNP:rs113994098)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:15929042, ECO:0000269|PubMed:18828154, FT ECO:0000269|PubMed:19307547, ECO:0000269|PubMed:20400524, FT ECO:0000269|PubMed:22000311, ECO:0000269|PubMed:30552426" FT /id="VAR_023675" FT VARIANT 852 FT /note="R -> C (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088688" FT VARIANT 853 FT /note="R -> W (in PEOB1; with absence of progressive FT external ophthalmoplegia; dbSNP:rs121918053)" FT /evidence="ECO:0000269|PubMed:16401742, FT ECO:0000269|PubMed:16634032" FT /id="VAR_058889" FT VARIANT 864 FT /note="N -> S (in MTDPS4B; dbSNP:rs121918050)" FT /evidence="ECO:0000269|PubMed:12825077" FT /id="VAR_023676" FT VARIANT 879 FT /note="Q -> H (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058890" FT VARIANT 885 FT /note="T -> S (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058891" FT VARIANT 889 FT /note="A -> T (in PEOB1; dbSNP:rs763393580)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023677" FT VARIANT 914 FT /note="T -> P (in MTDPS4A; dbSNP:rs139590686)" FT /evidence="ECO:0000269|PubMed:16621917, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154" FT /id="VAR_058892" FT VARIANT 923 FT /note="G -> D (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023678" FT VARIANT 932 FT /note="H -> Y (in SANDO and PEOB1; sporadic case; FT dbSNP:rs121918048)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:14745080" FT /id="VAR_023679" FT VARIANT 943 FT /note="R -> C (in PEOB1; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:21301859" FT /id="VAR_088689" FT VARIANT 943 FT /note="R -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023680" FT VARIANT 953 FT /note="R -> C (in PEOA1; dbSNP:rs11546842)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023681" FT VARIANT 955 FT /note="Y -> C (in PEOA1, PEOB1 and SANDO; 45-fold decrease FT in apparent binding affinity for the incoming nucleoside FT triphosphate; 2-fold less accurate for basepair FT substitutions than wild-type; dbSNP:rs113994099)" FT /evidence="ECO:0000269|PubMed:11431686, FT ECO:0000269|PubMed:11897778, ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:12565911, ECO:0000269|PubMed:15351195" FT /id="VAR_012156" FT VARIANT 957 FT /note="A -> P (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:15689359" FT /id="VAR_058893" FT VARIANT 957 FT /note="A -> S (in PEOA1; dbSNP:rs121918051)" FT /evidence="ECO:0000269|PubMed:12210792" FT /id="VAR_023682" FT VARIANT 966 FT /note="L -> R (in MTDPS4A; likely pathogenic)" FT /evidence="ECO:0000269|PubMed:22000311" FT /id="VAR_088690" FT VARIANT 1047 FT /note="R -> Q (in PEOB1; sporadic case; dbSNP:rs768028281)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023683" FT VARIANT 1051 FT /note="G -> R (in SANDO; dbSNP:rs121918049)" FT /evidence="ECO:0000269|PubMed:14745080" FT /id="VAR_023684" FT VARIANT 1076 FT /note="G -> V (in PEOB1)" FT /evidence="ECO:0000269|PubMed:12975295" FT /id="VAR_023685" FT VARIANT 1096 FT /note="R -> C (in PEOB1 and MTDPS4A; dbSNP:rs201732356)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:25129007" FT /id="VAR_023686" FT VARIANT 1096 FT /note="R -> H (in MTDPS4A; dbSNP:rs368435864)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058894" FT VARIANT 1104 FT /note="S -> C (in PEOB1; sporadic case; FT dbSNP:rs1010372555)" FT /evidence="ECO:0000269|PubMed:12707443" FT /id="VAR_023687" FT VARIANT 1105 FT /note="A -> T (in PEOB1; dbSNP:rs753410045)" FT /evidence="ECO:0000269|PubMed:15351195" FT /id="VAR_023688" FT VARIANT 1106 FT /note="V -> I (in PEOB1)" FT /evidence="ECO:0000269|PubMed:15349879" FT /id="VAR_023689" FT VARIANT 1110 FT /note="H -> Y (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058895" FT VARIANT 1134 FT /note="H -> R (in MTDPS4A)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_058896" FT VARIANT 1136 FT /note="E -> K (in MTDPS4A; dbSNP:rs56047213)" FT /evidence="ECO:0000269|PubMed:18828154" FT /id="VAR_065092" FT VARIANT 1142 FT /note="R -> W (in dbSNP:rs2307442)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_014908" FT VARIANT 1143 FT /note="E -> G (in dbSNP:rs2307441)" FT /evidence="ECO:0000269|PubMed:14635118, FT ECO:0000269|PubMed:15477547, ECO:0000269|PubMed:15689359, FT ECO:0000269|PubMed:16080118, ECO:0000269|PubMed:16639411, FT ECO:0000269|PubMed:18828154, ECO:0000269|Ref.4" FT /id="VAR_014909" FT VARIANT 1146 FT /note="R -> C (in PEOB1; uncertain significance; FT dbSNP:rs2307440)" FT /evidence="ECO:0000269|PubMed:16401742, ECO:0000269|Ref.4" FT /id="VAR_014910" FT VARIANT 1176 FT /note="S -> L (in PEOA1; dbSNP:rs776031396)" FT /evidence="ECO:0000269|PubMed:12210792, FT ECO:0000269|PubMed:15349879" FT /id="VAR_023690" FT VARIANT 1184 FT /note="D -> N (in PEOB1; dbSNP:rs1131691575)" FT /evidence="ECO:0000269|PubMed:16401742" FT /id="VAR_058897" FT VARIANT 1186 FT /note="D -> H (in PEOA1)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065119" FT VARIANT 1191 FT /note="K -> N (in MTDPS4A; dbSNP:rs1085307741)" FT /evidence="ECO:0000269|PubMed:16621917" FT /id="VAR_058898" FT VARIANT 1236 FT /note="Q -> H (in dbSNP:rs3087374)" FT /evidence="ECO:0000269|PubMed:12975295, FT ECO:0000269|PubMed:14635118, ECO:0000269|PubMed:15917273, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18828154, FT ECO:0000269|Ref.4" FT /id="VAR_014911" FT MUTAGEN 198 FT /note="D->A: Abolishes exonuclease activity; when FT associated with A-200. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-200. FT Significantly increases mitochondrial DNA mutation FT frequency. Does not affect DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 200 FT /note="E->A: Abolishes exonuclease activity; when FT associated with A-198. Decreases polymerase exonucleolytic FT proofreading by 30-fold for the T:G mismatch and by 14-fold FT for the A:A mismatch; when associated with A-198." FT /evidence="ECO:0000269|PubMed:11477093, FT ECO:0000269|PubMed:11504725, ECO:0000269|PubMed:37202477" FT MUTAGEN 274 FT /note="D->A: Unable to idle at the 5'-end of the nascent FT DNA strand. Continues DNA synthesis into double-stranded FT DNA past the 5'-end creating a flap structure that cannot FT be ligated." FT /evidence="ECO:0000269|PubMed:26095671" FT MUTAGEN 498 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 499 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 501 FT /note="K->C: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:26056153" FT MUTAGEN 543..558 FT /note="Missing: Markedly decreases the stimulation by FT POLG2, resulting in impaired processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 549 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 552 FT /note="L->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 553 FT /note="K->N: Decreases processive DNA synthesis." FT /evidence="ECO:0000269|PubMed:19837034" FT MUTAGEN 853 FT /note="R->A: Abolishes primer DNA extention in the presence FT of dNTPs. Impairs intrinsic polymerase processivity. FT Enhances exonuclease activity leading to primer DNA FT degradation." FT /evidence="ECO:0000269|PubMed:37202477" FT MUTAGEN 890 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT MUTAGEN 1135 FT /note="D->N: Abolishes DNA polymerase activity." FT /evidence="ECO:0000269|PubMed:10827171" FT HELIX 73..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 76..78 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 81..87 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 97..110 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 114..116 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 135..157 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 172..178 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 180..182 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 184..186 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 193..200 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 203..205 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 207..210 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 211..215 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 220..224 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 226..229 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 237..239 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 241..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..251 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 254..256 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 260..262 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 265..270 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 271..275 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 279..282 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 283..285 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 290..293 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 294..300 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 306..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 347..350 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 356..363 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 376..379 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 382..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 389..417 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 421..430 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 435..438 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 440..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..481 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 483..487 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:5C51" FT STRAND 519..521 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 538..553 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 554..558 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 559..561 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 567..569 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 571..575 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 587..589 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 594..598 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 599..602 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 606..609 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 610..615 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 616..618 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 619..624 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 628..630 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 636..644 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 648..650 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 651..662 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 716..721 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 739..742 FT /evidence="ECO:0007829|PDB:8D3R" FT STRAND 743..745 FT /evidence="ECO:0007829|PDB:4ZTU" FT STRAND 748..751 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 755..757 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 765..767 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 768..770 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 771..775 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 778..780 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 782..784 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 787..809 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 814..816 FT /evidence="ECO:0007829|PDB:8D42" FT HELIX 818..820 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 823..826 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 833..835 FT /evidence="ECO:0007829|PDB:8V5R" FT STRAND 837..840 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 845..848 FT /evidence="ECO:0007829|PDB:4ZTU" FT TURN 849..851 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 853..855 FT /evidence="ECO:0007829|PDB:4ZTU" FT HELIX 859..861 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 867..869 FT /evidence="ECO:0007829|PDB:8D37" FT HELIX 872..877 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 884..890 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 894..907 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 909..911 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 915..922 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 925..928 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 931..938 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 943..954 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 959..969 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 971..973 FT /evidence="ECO:0007829|PDB:8V5D" FT HELIX 975..989 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 991..993 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 997..999 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1001..1009 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1010..1013 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1027..1030 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1033..1035 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 1037..1040 FT /evidence="ECO:0007829|PDB:3IKM" FT TURN 1041..1046 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 1050..1052 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1055..1066 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1067..1069 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1073..1075 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1081..1083 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 1085..1087 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1089..1092 FT /evidence="ECO:0007829|PDB:8D3R" FT HELIX 1093..1122 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1127..1132 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1134..1142 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1143..1145 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1146..1167 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1175..1177 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1183..1188 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1191..1194 FT /evidence="ECO:0007829|PDB:8D33" FT STRAND 1202..1204 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 1206..1209 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1216..1218 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 1220..1227 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 1232..1235 FT /evidence="ECO:0007829|PDB:3IKM" SQ SEQUENCE 1239 AA; 139562 MW; 2D9ECCD75AD6E01E CRC64; MSRLLWRKVA GATVGPGPVP APGRWVSSSV PASDPSDGQR RRQQQQQQQQ QQQQQPQQPQ VLSSEGGQLR HNPLDIQMLS RGLHEQIFGQ GGEMPGEAAV RRSVEHLQKH GLWGQPAVPL PDVELRLPPL YGDNLDQHFR LLAQKQSLPY LEAANLLLQA QLPPKPPAWA WAEGWTRYGP EGEAVPVAIP EERALVFDVE VCLAEGTCPT LAVAISPSAW YSWCSQRLVE ERYSWTSQLS PADLIPLEVP TGASSPTQRD WQEQLVVGHN VSFDRAHIRE QYLIQGSRMR FLDTMSMHMA ISGLSSFQRS LWIAAKQGKH KVQPPTKQGQ KSQRKARRGP AISSWDWLDI SSVNSLAEVH RLYVGGPPLE KEPRELFVKG TMKDIRENFQ DLMQYCAQDV WATHEVFQQQ LPLFLERCPH PVTLAGMLEM GVSYLPVNQN WERYLAEAQG TYEELQREMK KSLMDLANDA CQLLSGERYK EDPWLWDLEW DLQEFKQKKA KKVKKEPATA SKLPIEGAGA PGDPMDQEDL GPCSEEEEFQ QDVMARACLQ KLKGTTELLP KRPQHLPGHP GWYRKLCPRL DDPAWTPGPS LLSLQMRVTP KLMALTWDGF PLHYSERHGW GYLVPGRRDN LAKLPTGTTL ESAGVVCPYR AIESLYRKHC LEQGKQQLMP QEAGLAEEFL LTDNSAIWQT VEELDYLEVE AEAKMENLRA AVPGQPLALT ARGGPKDTQP SYHHGNGPYN DVDIPGCWFF KLPHKDGNSC NVGSPFAKDF LPKMEDGTLQ AGPGGASGPR ALEINKMISF WRNAHKRISS QMVVWLPRSA LPRAVIRHPD YDEEGLYGAI LPQVVTAGTI TRRAVEPTWL TASNARPDRV GSELKAMVQA PPGYTLVGAD VDSQELWIAA VLGDAHFAGM HGCTAFGWMT LQGRKSRGTD LHSKTATTVG ISREHAKIFN YGRIYGAGQP FAERLLMQFN HRLTQQEAAE KAQQMYAATK GLRWYRLSDE GEWLVRELNL PVDRTEGGWI SLQDLRKVQR ETARKSQWKK WEVVAERAWK GGTESEMFNK LESIATSDIP RTPVLGCCIS RALEPSAVQE EFMTSRVNWV VQSSAVDYLH LMLVAMKWLF EEFAIDGRFC ISIHDEVRYL VREEDRYRAA LALQITNLLT RCMFAYKLGL NDLPQSVAFF SAVDIDRCLR KEVTMDCKTP SNPTGMERRY GIPQGEALDI YQIIELTKGS LEKRSQPGP // ID DPOG2_HUMAN Reviewed; 485 AA. AC Q9UHN1; O00419; Q0IJ81; Q96GW2; Q9UK35; Q9UK94; DT 16-NOV-2001, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 28-JAN-2026, entry version 201. DE RecName: Full=DNA polymerase subunit gamma-2; DE AltName: Full=DNA polymerase gamma accessory 55 kDa subunit; DE Short=p55 {ECO:0000303|PubMed:10608893}; DE AltName: Full=Mitochondrial DNA polymerase accessory subunit; DE AltName: Full=MtPolB; DE AltName: Full=PolG-beta; DE Flags: Precursor; GN Name=POLG2 {ECO:0000303|PubMed:30157269, ECO:0000312|HGNC:HGNC:9180}; GN Synonyms=MTPOLB; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Cerebellum; RX PubMed=10608893; DOI=10.1074/jbc.274.53.38197; RA Lim S.E., Longley M.J., Copeland W.C.; RT "The mitochondrial p55 accessory subunit of human DNA polymerase gamma RT enhances DNA binding, promotes processive DNA synthesis, and confers N- RT ethylmaleimide resistance."; RL J. Biol. Chem. 274:38197-38203(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT THR-169. RX PubMed=10666468; DOI=10.1093/nar/28.5.1237; RA Carrodeguas J.A., Bogenhagen D.F.; RT "Protein sequences conserved in prokaryotic aminoacyl-tRNA synthetases are RT important for the activity of the processivity factor of human RT mitochondrial DNA polymerase."; RL Nucleic Acids Res. 28:1237-1244(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10677218; DOI=10.1021/bi992104w; RA Johnson A.A., Tsai Y.-C., Graves S.W., Johnson K.A.; RT "Human mitochondrial DNA polymerase holoenzyme: reconstitution and RT characterization."; RL Biochemistry 39:1702-1708(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS THR-169 AND ALA-416. RC TISSUE=Cervix, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] OF 114-485. RX PubMed=9153213; DOI=10.1074/jbc.272.21.13640; RA Wang Y., Farr C.L., Kaguni L.S.; RT "Accessory subunit of mitochondrial DNA polymerase from Drosophila embryos. RT Cloning, molecular analysis, and association in the native enzyme."; RL J. Biol. Chem. 272:13640-13646(1997). RN [6] RP FUNCTION, AND SUBUNIT. RX PubMed=11477093; DOI=10.1074/jbc.m106045200; RA Johnson A.A., Johnson K.A.; RT "Fidelity of nucleotide incorporation by human mitochondrial DNA RT polymerase."; RL J. Biol. Chem. 276:38090-38096(2001). RN [7] RP FUNCTION, AND SUBUNIT. RX PubMed=11477094; DOI=10.1074/jbc.m106046200; RA Johnson A.A., Johnson K.A.; RT "Exonuclease proofreading by human mitochondrial DNA polymerase."; RL J. Biol. Chem. 276:38097-38107(2001). RN [8] RP FUNCTION, AND SUBUNIT. RX PubMed=11504725; DOI=10.1074/jbc.m105230200; RA Longley M.J., Nguyen D., Kunkel T.A., Copeland W.C.; RT "The fidelity of human DNA polymerase gamma with and without exonucleolytic RT proofreading and the p55 accessory subunit."; RL J. Biol. Chem. 276:38555-38562(2001). RN [9] RP FUNCTION, AND SUBUNIT. RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-38, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [12] RP FUNCTION, AND CHARACTERIZATION OF VARIANT MTDPS16 TRP-182. RX PubMed=30157269; DOI=10.1371/journal.pone.0203198; RA Hoff K.E., DeBalsi K.L., Sanchez-Quintero M.J., Longley M.J., Hirano M., RA Naini A.B., Copeland W.C.; RT "Characterization of the human homozygous R182W POLG2 mutation in RT mitochondrial DNA depletion syndrome."; RL PLoS ONE 13:e0203198-e0203198(2018). RN [13] RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 1-146 AND 181-485, FUNCTION, AND RP SUBUNIT. RX PubMed=19837034; DOI=10.1016/j.cell.2009.07.050; RA Lee Y.S., Kennedy W.D., Yin Y.W.; RT "Structural insight into processive human mitochondrial DNA synthesis and RT disease-related polymerase mutations."; RL Cell 139:312-324(2009). RN [14] RP X-RAY CRYSTALLOGRAPHY (3.30 ANGSTROMS) OF 26-485, FUNCTION, AND SUBUNIT. RX PubMed=26056153; DOI=10.15252/embj.201591520; RA Szymanski M.R., Kuznetsov V.B., Shumate C., Meng Q., Lee Y.S., Patel G., RA Patel S., Yin Y.W.; RT "Structural basis for processivity and antiviral drug toxicity in human RT mitochondrial DNA replicase."; RL EMBO J. 34:1959-1970(2015). RN [15] RP STRUCTURE BY ELECTRON MICROSCOPY (2.46 ANGSTROMS), FUNCTION, AND SUBUNIT. RX PubMed=37202477; DOI=10.1038/s41594-023-00980-2; RA Park J., Herrmann G.K., Mitchell P.G., Sherman M.B., Yin Y.W.; RT "Polgamma coordinates DNA synthesis and proofreading to ensure RT mitochondrial genome integrity."; RL Nat. Struct. Mol. Biol. 30:812-823(2023). RN [16] RP VARIANT PEOA4 GLU-451, AND CHARACTERIZATION OF VARIANT PEOA4 GLU-451. RX PubMed=16685652; DOI=10.1086/504303; RA Longley M.J., Clark S., Man C.Y.W., Hudson G., Durham S.E., Taylor R.W., RA Nightingale S., Turnbull D.M., Copeland W.C., Chinnery P.F.; RT "Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive RT external ophthalmoplegia."; RL Am. J. Hum. Genet. 78:1026-1034(2006). RN [17] RP VARIANT ALA-416, AND CHARACTERIZATION OF VARIANT ALA-416. RX PubMed=18195150; DOI=10.1001/archneurol.2007.9; RA Ferraris S., Clark S., Garelli E., Davidzon G., Moore S.A., Kardon R.H., RA Bienstock R.J., Longley M.J., Mancuso M., Gutierrez Rios P., Hirano M., RA Copeland W.C., DiMauro S.; RT "Progressive external ophthalmoplegia and vision and hearing loss in a RT patient with mutations in POLG2 and OPA1."; RL Arch. Neurol. 65:125-131(2008). RN [18] RP VARIANT MTDPS16 TRP-182, AND INVOLVEMENT IN MTDPS16. RX PubMed=27592148; DOI=10.1016/j.ejmg.2016.08.012; RA Varma H., Faust P.L., Iglesias A.D., Lagana S.M., Wou K., Hirano M., RA DiMauro S., Mansukani M.M., Hoff K.E., Nagy P.L., Copeland W.C., RA Naini A.B.; RT "Whole exome sequencing identifies a homozygous POLG2 missense variant in RT an infant with fulminant hepatic failure and mitochondrial DNA depletion."; RL Eur. J. Med. Genet. 59:540-545(2016). RN [19] RP VARIANT MTDPS16B TYR-433, INVOLVEMENT IN MTDPS16B, CHARACTERIZATION OF RP VARIANT MTDPS16B TYR-433, AND FUNCTION. RX PubMed=31778857; DOI=10.1016/j.ejmg.2019.103821; RA Dosekova P., Dubiel A., Karlowicz A., Zietkiewicz S., Rydzanicz M., RA Habalova V., Pienkowski V.M., Skirkova M., Han V., Mosejova A., RA Gdovinova Z., Kaliszewska M., Tonska K., Szymanski M.R., Skorvanek M., RA Ploski R.; RT "Whole exome sequencing identifies a homozygous POLG2 missense variant in RT an adult patient presenting with optic atrophy, movement disorders, RT premature ovarian failure and mitochondrial DNA depletion."; RL Eur. J. Med. Genet. 63:103821-103821(2020). CC -!- FUNCTION: Accessory subunit of DNA polymerase gamma solely responsible CC for replication of mitochondrial DNA (mtDNA). Acts as an allosteric CC regulator of the holoenzyme activities. Enhances the polymerase CC activity and the processivity of POLG by increasing its interactions CC with the DNA template. Suppresses POLG exonucleolytic proofreading CC especially toward homopolymeric templates bearing mismatched termini. CC Binds to single-stranded DNA. {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:30157269, CC ECO:0000269|PubMed:31778857, ECO:0000269|PubMed:37202477}. CC -!- SUBUNIT: Heterotrimer composed of a catalytic subunit and a homodimer CC of accessory subunits (POLG:POLG2). {ECO:0000269|PubMed:11477093, CC ECO:0000269|PubMed:11477094, ECO:0000269|PubMed:11504725, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:19837034, CC ECO:0000269|PubMed:26056153, ECO:0000269|PubMed:37202477}. CC -!- INTERACTION: CC Q9UHN1; P54098: POLG; NbExp=15; IntAct=EBI-852642, EBI-852624; CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000250|UniProtKB:P54098}. CC Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000250|UniProtKB:P54098}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 4 (PEOA4) [MIM:610131]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:16685652}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 16, hepatic type CC (MTDPS16) [MIM:618528]: An autosomal recessive disorder characterized CC by poor feeding, difficulty breathing, abdominal distention, an CC abnormal carnitine profile, metabolic acidosis and hepatic failure in CC the neonatal period. Severe mtDNA depletion is observed in liver and CC muscle biopsies. {ECO:0000269|PubMed:27592148, CC ECO:0000269|PubMed:30157269}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type CC (MTDPS16B) [MIM:619425]: An autosomal recessive disorder characterized CC by childhood onset of progressive neuroophthalmic manifestations with CC optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia, and CC generalized chorea associated with mtDNA depletion. CC {ECO:0000269|PubMed:31778857}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF142992; AAD50382.1; -; mRNA. DR EMBL; AF177201; AAD56640.1; -; mRNA. DR EMBL; AF184344; AAD56542.1; -; mRNA. DR EMBL; BC000913; AAH00913.2; -; mRNA. DR EMBL; BC009194; AAH09194.1; -; mRNA. DR EMBL; U94703; AAC51321.1; -; mRNA. DR CCDS; CCDS32706.1; -. DR RefSeq; NP_009146.2; NM_007215.4. DR PDB; 2G4C; X-ray; 3.15 A; A/B/C/D=26-485. DR PDB; 3IKL; X-ray; 3.10 A; A/B=1-146, A/B=181-485. DR PDB; 3IKM; X-ray; 3.24 A; B/C/E/F=59-485. DR PDB; 4ZTU; X-ray; 3.30 A; B/C=26-485. DR PDB; 4ZTZ; X-ray; 3.44 A; B/C=26-485. DR PDB; 5C51; X-ray; 3.43 A; B/C=1-485. DR PDB; 5C52; X-ray; 3.64 A; B/C=1-485. DR PDB; 5C53; X-ray; 3.57 A; B/C=1-485. DR PDB; 8D33; EM; 2.46 A; B/C=1-485. DR PDB; 8D37; EM; 2.65 A; B/C=1-485. DR PDB; 8D3R; EM; 3.04 A; B/C=1-485. DR PDB; 8D42; EM; 2.91 A; B/C=1-485. DR PDB; 8G5I; EM; 2.75 A; B/C=1-485. DR PDB; 8G5J; EM; 2.63 A; B/C=1-485. DR PDB; 8G5K; EM; 2.90 A; B/C=1-485. DR PDB; 8G5L; EM; 3.00 A; B/C=1-485. DR PDB; 8G5M; EM; 2.58 A; B/C=1-485. DR PDB; 8G5N; EM; 2.73 A; B/C=1-485. DR PDB; 8G5O; EM; 2.61 A; B/C=1-485. DR PDB; 8G5P; EM; 2.78 A; B/C=1-485. DR PDB; 8T7E; EM; 3.08 A; B/C=1-485. DR PDB; 8UDK; X-ray; 3.43 A; B/C=1-485. DR PDB; 8UDL; EM; 2.37 A; B/C=1-485. DR PDB; 8V54; EM; 4.10 A; B/C=26-485. DR PDB; 8V55; EM; 4.20 A; B/C=26-485. DR PDB; 8V5R; EM; 3.00 A; B/C=26-485. DR PDB; 9GGB; EM; 2.63 A; B/C=25-485. DR PDB; 9GGC; EM; 2.39 A; B/C=25-485. DR PDB; 9GGD; EM; 2.67 A; B/C=25-485. DR PDB; 9GGE; EM; 2.69 A; B/C=25-485. DR PDB; 9GGF; EM; 2.65 A; B/C=25-485. DR PDB; 9IBX; EM; 2.54 A; B/C=25-485. DR PDB; 9IBZ; EM; 3.08 A; B/C=25-485. DR PDB; 9IC0; EM; 3.24 A; B/C=25-485. DR PDBsum; 2G4C; -. DR PDBsum; 3IKL; -. DR PDBsum; 3IKM; -. DR PDBsum; 4ZTU; -. DR PDBsum; 4ZTZ; -. DR PDBsum; 5C51; -. DR PDBsum; 5C52; -. DR PDBsum; 5C53; -. DR PDBsum; 8D33; -. DR PDBsum; 8D37; -. DR PDBsum; 8D3R; -. DR PDBsum; 8D42; -. DR PDBsum; 8G5I; -. DR PDBsum; 8G5J; -. DR PDBsum; 8G5K; -. DR PDBsum; 8G5L; -. DR PDBsum; 8G5M; -. DR PDBsum; 8G5N; -. DR PDBsum; 8G5O; -. DR PDBsum; 8G5P; -. DR PDBsum; 8T7E; -. DR PDBsum; 8UDK; -. DR PDBsum; 8UDL; -. DR PDBsum; 8V54; -. DR PDBsum; 8V55; -. DR PDBsum; 8V5R; -. DR PDBsum; 9GGB; -. DR PDBsum; 9GGC; -. DR PDBsum; 9GGD; -. DR PDBsum; 9GGE; -. DR PDBsum; 9GGF; -. DR PDBsum; 9IBX; -. DR PDBsum; 9IBZ; -. DR PDBsum; 9IC0; -. DR AlphaFoldDB; Q9UHN1; -. DR EMDB; EMD-27154; -. DR EMDB; EMD-27155; -. DR EMDB; EMD-27163; -. DR EMDB; EMD-27172; -. DR EMDB; EMD-29745; -. DR EMDB; EMD-29746; -. DR EMDB; EMD-29747; -. DR EMDB; EMD-29748; -. DR EMDB; EMD-29749; -. DR EMDB; EMD-29750; -. DR EMDB; EMD-29751; -. DR EMDB; EMD-29752; -. DR EMDB; EMD-41091; -. DR EMDB; EMD-42150; -. DR EMDB; EMD-42842; -. DR EMDB; EMD-42979; -. DR EMDB; EMD-42980; -. DR EMDB; EMD-42984; -. DR EMDB; EMD-51326; -. DR EMDB; EMD-51327; -. DR EMDB; EMD-51328; -. DR EMDB; EMD-51329; -. DR EMDB; EMD-51330; -. DR EMDB; EMD-52815; -. DR EMDB; EMD-52819; -. DR EMDB; EMD-52823; -. DR SMR; Q9UHN1; -. DR BioGRID; 116398; 39. DR ComplexPortal; CPX-2093; Mitochondrial DNA polymerase gamma complex. DR FunCoup; Q9UHN1; 851. DR IntAct; Q9UHN1; 37. DR MINT; Q9UHN1; -. DR STRING; 9606.ENSP00000442563; -. DR ChEMBL; CHEMBL3430903; -. DR DrugBank; DB12151; Brincidofovir. DR iPTMnet; Q9UHN1; -. DR PhosphoSitePlus; Q9UHN1; -. DR BioMuta; POLG2; -. DR DMDM; 17367139; -. DR jPOST; Q9UHN1; -. DR MassIVE; Q9UHN1; -. DR PaxDb; 9606-ENSP00000442563; -. DR PeptideAtlas; Q9UHN1; -. DR ProteomicsDB; 84382; -. DR Pumba; Q9UHN1; -. DR Antibodypedia; 50586; 171 antibodies from 29 providers. DR DNASU; 11232; -. DR Ensembl; ENST00000539111.7; ENSP00000442563.2; ENSG00000256525.9. DR GeneID; 11232; -. DR KEGG; hsa:11232; -. DR MANE-Select; ENST00000539111.7; ENSP00000442563.2; NM_007215.4; NP_009146.2. DR UCSC; uc002jei.4; human. DR AGR; HGNC:9180; -. DR ClinPGx; PA33501; -. DR CTD; 11232; -. DR DisGeNET; 11232; -. DR GeneCards; POLG2; -. DR HGNC; HGNC:9180; POLG2. DR HPA; ENSG00000256525; Low tissue specificity. DR MalaCards; POLG2; -. DR MIM; 604983; gene. DR MIM; 610131; phenotype. DR MIM; 618528; phenotype. DR MIM; 619425; phenotype. DR OpenTargets; ENSG00000256525; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR VEuPathDB; HostDB:ENSG00000256525; -. DR eggNOG; KOG2298; Eukaryota. DR GeneTree; ENSGT00940000153759; -. DR HOGENOM; CLU_055833_0_0_1; -. DR InParanoid; Q9UHN1; -. DR OMA; WGQEVLE; -. DR OrthoDB; 57698at2759; -. DR PAN-GO; Q9UHN1; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q9UHN1; -. DR BRENDA; 2.7.7.7; 2681. DR PathwayCommons; Q9UHN1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q9UHN1; -. DR SIGNOR; Q9UHN1; -. DR Agora; ENSG00000256525; -. DR BioGRID-ORCS; 11232; 326 hits in 1164 CRISPR screens. DR ChiTaRS; POLG2; human. DR EvolutionaryTrace; Q9UHN1; -. DR GeneWiki; POLG2; -. DR GenomeRNAi; 11232; -. DR Pharos; Q9UHN1; Tbio. DR PRO; PR:Q9UHN1; -. DR Proteomes; UP000005640; Chromosome 17. DR RNAct; Q9UHN1; protein. DR Bgee; ENSG00000256525; Expressed in secondary oocyte and 177 other cell types or tissues. DR ExpressionAtlas; Q9UHN1; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005760; C:gamma DNA polymerase complex; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; IDA:ComplexPortal. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0070182; F:DNA polymerase binding; IPI:UniProtKB. DR GO; GO:0030337; F:DNA polymerase processivity factor activity; IDA:UniProtKB. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IEA:Ensembl. DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:UniProtKB. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0006264; P:mitochondrial DNA replication; IDA:FlyBase. DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl. DR GO; GO:1900264; P:positive regulation of DNA-directed DNA polymerase activity; IDA:UniProtKB. DR CDD; cd02426; Pol_gamma_b_Cterm; 1. DR FunFam; 3.40.50.800:FF:000014; Putative dna polymerase subunit gamma-2 mitochondrial; 1. DR Gene3D; 3.40.50.800; Anticodon-binding domain; 1. DR Gene3D; 3.30.930.10; Bira Bifunctional Protein, Domain 2; 1. DR InterPro; IPR045864; aa-tRNA-synth_II/BPL/LPL. DR InterPro; IPR004154; Anticodon-bd. DR InterPro; IPR036621; Anticodon-bd_dom_sf. DR InterPro; IPR027031; Gly-tRNA_synthase/POLG2. DR InterPro; IPR042064; POLG2_C. DR PANTHER; PTHR10745:SF8; DNA POLYMERASE SUBUNIT GAMMA-2, MITOCHONDRIAL; 1. DR PANTHER; PTHR10745; GLYCYL-TRNA SYNTHETASE/DNA POLYMERASE SUBUNIT GAMMA-2; 1. DR Pfam; PF03129; HGTP_anticodon; 1. DR SUPFAM; SSF52954; Class II aaRS ABD-related; 1. DR SUPFAM; SSF55681; Class II aaRS and biotin synthetases; 1. PE 1: Evidence at protein level; KW 3D-structure; Disease variant; DNA replication; DNA-binding; Mitochondrion; KW Mitochondrion nucleoid; Phosphoprotein; Primary mitochondrial disease; KW Progressive external ophthalmoplegia; Proteomics identification; KW Reference proteome; Transit peptide. FT TRANSIT 1..? FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN ?..485 FT /note="DNA polymerase subunit gamma-2" FT /id="PRO_0000007314" FT REGION 28..65 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 46..58 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 38 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT VARIANT 169 FT /note="A -> T (in dbSNP:rs1427463)" FT /evidence="ECO:0000269|PubMed:10666468, FT ECO:0000269|PubMed:15489334" FT /id="VAR_032028" FT VARIANT 182 FT /note="R -> W (in MTDPS16; decreased function in FT mitochondrial DNA replication; decreased protein stability; FT no effect on DNA binding; dbSNP:rs886037843)" FT /evidence="ECO:0000269|PubMed:27592148, FT ECO:0000269|PubMed:30157269" FT /id="VAR_078773" FT VARIANT 416 FT /note="G -> A (no functional deficit; dbSNP:rs17850455)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:18195150" FT /id="VAR_032029" FT VARIANT 433 FT /note="D -> Y (in MTDPS16B; decreased DNA polymerase FT processivity factor activity; results in decreased FT stability; affects the secondary structure as shown by FT circular dichroism spectroscopy; dbSNP:rs2144120492)" FT /evidence="ECO:0000269|PubMed:31778857" FT /id="VAR_086017" FT VARIANT 451 FT /note="G -> E (in PEOA4; affects stimulation of the FT catalytic subunit; dbSNP:rs104894632)" FT /evidence="ECO:0000269|PubMed:16685652" FT /id="VAR_029364" FT CONFLICT 114..124 FT /note="WWTSVVVFREQ -> MVDLGGGVHGA (in Ref. 5; AAC51321)" FT /evidence="ECO:0000305" FT CONFLICT 122 FT /note="R -> T (in Ref. 3; AAD56542)" FT /evidence="ECO:0000305" FT CONFLICT 136 FT /note="G -> S (in Ref. 3; AAD56542 and 5; AAC51321)" FT /evidence="ECO:0000305" FT CONFLICT 287..292 FT /note="NKLYYN -> TNFTTI (in Ref. 5; AAC51321)" FT /evidence="ECO:0000305" FT HELIX 65..75 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 78..80 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 83..85 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 88..93 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 101..118 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 119..121 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 125..127 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 132..134 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 135..137 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 138..141 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 144..146 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 152..156 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 157..159 FT /evidence="ECO:0007829|PDB:2G4C" FT HELIX 165..169 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 170..176 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:8V5R" FT HELIX 186..190 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 193..196 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 197..200 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 206..218 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 224..226 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 230..243 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 245..247 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 248..266 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 270..272 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 273..279 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 281..284 FT /evidence="ECO:0007829|PDB:3IKL" FT STRAND 285..293 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 296..308 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 309..314 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 319..321 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 324..326 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 329..331 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 334..341 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 342..353 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 359..361 FT /evidence="ECO:0007829|PDB:3IKM" FT HELIX 362..365 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 376..378 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 379..381 FT /evidence="ECO:0007829|PDB:3IKM" FT STRAND 383..387 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 392..408 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 413..415 FT /evidence="ECO:0007829|PDB:8D33" FT HELIX 416..418 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 419..421 FT /evidence="ECO:0007829|PDB:3IKL" FT HELIX 425..434 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 438..443 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 445..450 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 452..457 FT /evidence="ECO:0007829|PDB:8UDL" FT TURN 458..460 FT /evidence="ECO:0007829|PDB:8UDL" FT STRAND 463..467 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 468..470 FT /evidence="ECO:0007829|PDB:8UDL" FT HELIX 471..482 FT /evidence="ECO:0007829|PDB:8UDL" SQ SEQUENCE 485 AA; 54911 MW; B99734BFEA249192 CRC64; MRSRVAVRAC HKVCRCLLSG FGGRVDAGQP ELLTERSSPK GGHVKSHAEL EGNGEHPEAP GSGEGSEALL EICQRRHFLS GSKQQLSRDS LLSGCHPGFG PLGVELRKNL AAEWWTSVVV FREQVFPVDA LHHKPGPLLP GDSAFRLVSA ETLREILQDK ELSKEQLVAF LENVLKTSGK LRENLLHGAL EHYVNCLDLV NKRLPYGLAQ IGVCFHPVFD TKQIRNGVKS IGEKTEASLV WFTPPRTSNQ WLDFWLRHRL QWWRKFAMSP SNFSSSDCQD EEGRKGNKLY YNFPWGKELI ETLWNLGDHE LLHMYPGNVS KLHGRDGRKN VVPCVLSVNG DLDRGMLAYL YDSFQLTENS FTRKKNLHRK VLKLHPCLAP IKVALDVGRG PTLELRQVCQ GLFNELLENG ISVWPGYLET MQSSLEQLYS KYDEMSILFT VLVTETTLEN GLIHLRSRDT TMKEMMHISK LKDFLIKYIS SAKNV // ID PEO1_HUMAN Reviewed; 684 AA. AC Q96RR1; B2CQL2; Q6MZX2; Q6PJP5; Q96RR0; DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 28-JAN-2026, entry version 193. DE RecName: Full=Twinkle mtDNA helicase {ECO:0000312|HGNC:HGNC:1160}; DE EC=5.6.2.3 {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550}; DE AltName: Full=Progressive external ophthalmoplegia 1 protein; DE AltName: Full=T7 gp4-like protein with intramitochondrial nucleoid localization; DE AltName: Full=T7-like mitochondrial DNA helicase; DE AltName: Full=Twinkle protein, mitochondrial {ECO:0000305}; DE Flags: Precursor; GN Name=TWNK {ECO:0000312|HGNC:HGNC:1160}; Synonyms=C10orf2, PEO1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, RP SUBCELLULAR LOCATION, VARIANT ILE-368, AND VARIANTS PEOA3 LEU-315; PRO-354; RP THR-359; THR-367; PRO-369; GLN-374; PRO-381; CYS-474 AND PRO-475. RX PubMed=11431692; DOI=10.1038/90058; RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RT "Human mitochondrial DNA deletions associated with mutations in the gene RT for Twinkle, a phage T7 gene 4-like protein localized in mitochondria."; RL Nat. Genet. 28:223-231(2001). RN [2] RP ERRATUM OF PUBMED:11431692. RA Spelbrink J.N., Li F.-Y., Tiranti V., Nikali K., Yuan Q.-P., Tariq M., RA Wanrooij S., Garrido N., Comi G., Morandi L., Santoro L., Toscano A., RA Fabrizi G.-M., Somer H., Croxen R., Beeson D., Poulton J., Suomalainen A., RA Jacobs H.T., Zeviani M., Larsson C.; RL Nat. Genet. 29:100-100(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RC TISSUE=Fetal brain; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-348; ILE-368 AND RP LYS-634. RG NIEHS SNPs program; RL Submitted (MAR-2008) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164054; DOI=10.1038/nature02462; RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L., RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K., RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L., RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P., RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P., RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N., RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A., RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C., RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D., RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C., RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K., RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A., RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S., RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S., RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A., RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P., RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y., RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D., RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 10."; RL Nature 429:375-381(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 132-582 (ISOFORM 2). RC TISSUE=Skin; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=12975372; DOI=10.1074/jbc.m306981200; RA Korhonen J.A., Gaspari M., Falkenberg M.; RT "TWINKLE has 5' -> 3' DNA helicase activity and is specifically stimulated RT by mitochondrial single-stranded DNA-binding protein."; RL J. Biol. Chem. 278:48627-48632(2003). RN [9] RP FUNCTION (ISOFORM 1), AND INTERACTION WITH POLG (ISOFORM 1). RX PubMed=15167897; DOI=10.1038/sj.emboj.7600257; RA Korhonen J.A., Pham X.H., Pellegrini M., Falkenberg M.; RT "Reconstitution of a minimal mtDNA replisome in vitro."; RL EMBO J. 23:2423-2429(2004). RN [10] RP TISSUE SPECIFICITY, AND COREGULATION WITH MRPL43. RX PubMed=15509589; DOI=10.1093/hmg/ddh342; RA Tyynismaa H., Sembongi H., Bokori-Brown M., Granycome C., Ashley N., RA Poulton J., Jalanko A., Spelbrink J.N., Holt I.J., Suomalainen A.; RT "Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA RT copy number."; RL Hum. Mol. Genet. 13:3219-3227(2004). RN [11] RP INTERACTION WITH LONP1. RX PubMed=14739292; DOI=10.1074/jbc.m309642200; RA Liu T., Lu B., Lee I., Ondrovicova G., Kutejova E., Suzuki C.K.; RT "DNA and RNA binding by the mitochondrial lon protease is regulated by RT nucleotide and protein substrate."; RL J. Biol. Chem. 279:13902-13910(2004). RN [12] RP POSSIBLE MECHANISM OF DELETION FORMATION. RX PubMed=15181170; DOI=10.1093/nar/gkh634; RA Wanrooij S., Luoma P., van Goethem G., van Broeckhoven C., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle and POLG defects enhance age-dependent accumulation of mutations RT in the control region of mtDNA."; RL Nucleic Acids Res. 32:3053-3064(2004). RN [13] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=17324440; DOI=10.1016/j.jmb.2007.01.079; RA Ziebarth T.D., Farr C.L., Kaguni L.S.; RT "Modular architecture of the hexameric human mitochondrial DNA helicase."; RL J. Mol. Biol. 367:1382-1391(2007). RN [14] RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT RP (ISOFORMS 1 AND 2), AND DOMAIN. RX PubMed=18039713; DOI=10.1093/nar/gkm1025; RA Farge G., Holmlund T., Khvorostova J., Rofougaran R., Hofer A., RA Falkenberg M.; RT "The N-terminal domain of TWINKLE contributes to single-stranded DNA RT binding and DNA helicase activities."; RL Nucleic Acids Res. 36:393-403(2008). RN [15] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), SUBUNIT (ISOFORM 1), RP SUBCELLULAR LOCATION, AND CHARACTERIZATION OF VARIANTS LEU-315; GLU-319; RP THR-359; PRO-369; GLN-374 AND CYS-474. RX PubMed=18971204; DOI=10.1093/hmg/ddn359; RA Goffart S., Cooper H.M., Tyynismaa H., Wanrooij S., Suomalainen A., RA Spelbrink J.N.; RT "Twinkle mutations associated with autosomal dominant progressive external RT ophthalmoplegia lead to impaired helicase function and in vivo mtDNA RT replication stalling."; RL Hum. Mol. Genet. 18:328-340(2009). RN [16] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), ACTIVITY REGULATION RP (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES (ISOFORM 1), SUBUNIT (ISOFORM RP 1), AND MUTAGENESIS OF LYS-421. RX PubMed=22383523; DOI=10.1074/jbc.m111.309468; RA Sen D., Nandakumar D., Tang G.Q., Patel S.S.; RT "Human mitochondrial DNA helicase TWINKLE is both an unwinding and RT annealing helicase."; RL J. Biol. Chem. 287:14545-14556(2012). RN [17] RP FUNCTION (ISOFORM 1), CATALYTIC ACTIVITY (ISOFORM 1), AND SUBUNIT (ISOFORM RP 1). RX PubMed=25824949; DOI=10.1093/nar/gkv189; RA Fernandez-Millan P., Lazaro M., Cansiz-Arda S., Gerhold J.M., Rajala N., RA Schmitz C.A., Silva-Espina C., Gil D., Bernado P., Valle M., RA Spelbrink J.N., Sola M.; RT "The hexameric structure of the human mitochondrial replicative helicase RT Twinkle."; RL Nucleic Acids Res. 43:4284-4295(2015). RN [18] RP FUNCTION (ISOFORM 1). RX PubMed=26887820; DOI=10.1093/nar/gkw098; RA Sen D., Patel G., Patel S.S.; RT "Homologous DNA strand exchange activity of the human mitochondrial DNA RT helicase TWINKLE."; RL Nucleic Acids Res. 44:4200-4210(2016). RN [19] RP FUNCTION (ISOFORM 1), AND CATALYTIC ACTIVITY (ISOFORM 1). RX PubMed=27226550; DOI=10.1074/jbc.m115.712026; RA Khan I., Crouch J.D., Bharti S.K., Sommers J.A., Carney S.M., RA Yakubovskaya E., Garcia-Diaz M., Trakselis M.A., Brosh R.M. Jr.; RT "Biochemical Characterization of the Human Mitochondrial Replicative RT Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY RT TO OVERCOME BLOCKADES TO DNA UNWINDING."; RL J. Biol. Chem. 291:14324-14339(2016). RN [20] RP SUBUNIT (ISOFORM 1), AND CHARACTERIZATION OF PEOA3 LEU-314; GLN-334; RP LEU-335; PRO-369 AND PRO-381. RX PubMed=30496414; DOI=10.1093/hmg/ddy415; RA Peter B., Farge G., Pardo-Hernandez C., Taangefjord S., Falkenberg M.; RT "Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE RT helicase."; RL Hum. Mol. Genet. 28:1090-1099(2019). RN [21] RP SUBCELLULAR LOCATION. RX PubMed=34950192; DOI=10.3389/fgene.2021.790521; RA So M., Stiban J., Ciesielski G.L., Hovde S.L., Kaguni L.S.; RT "Implications of Membrane Binding by the Fe-S Cluster-Containing N-Terminal RT Domain in the Drosophila Mitochondrial Replicative DNA Helicase."; RL Front. Genet. 12:790521-790521(2021). RN [22] {ECO:0007744|PDB:7T8B, ECO:0007744|PDB:7T8C} RP STRUCTURE BY ELECTRON MICROSCOPY (3.8 ANGSTROMS) OF 1-684 OF VARIANT RP LEU-315, CATALYTIC ACTIVITY, SUBUNIT, AND CHARACTERIZATION OF VARIANT RP LEU-315. RX PubMed=35914129; DOI=10.1073/pnas.2207459119; RA Riccio A.A., Bouvette J., Perera L., Longley M.J., Krahn J.M., RA Williams J.G., Dutcher R., Borgnia M.J., Copeland W.C.; RT "Structural insight and characterization of human Twinkle helicase in RT mitochondrial disease."; RL Proc. Natl. Acad. Sci. U.S.A. 119:e2207459119-e2207459119(2022). RN [23] RP VARIANTS PEOA3 LEU-335 AND TYR-369. RX PubMed=12163192; DOI=10.1016/s0022-510x(02)00190-9; RA Lewis S., Hutchison W., Thyagarajan D., Dahl H.-H.M.; RT "Clinical and molecular features of adPEO due to mutations in the Twinkle RT gene."; RL J. Neurol. Sci. 201:39-44(2002). RN [24] RP VARIANT ILE-368. RX PubMed=12557300; DOI=10.1002/ana.10430; RA Arenas J., Briem E., Dahl H.-H.M., Hutchison W., Lewis S., Martin M.A., RA Spelbrink H., Tiranti V., Jacobs H., Zeviani M.; RT "The V368I mutation in Twinkle does not segregate with AdPEO."; RL Ann. Neurol. 53:278-278(2003). RN [25] RP VARIANT PEO GLN-334. RX PubMed=12872260; DOI=10.1002/humu.10246; RA Van Goethem G., Loefgren A., Dermaut B., Ceuterick C., Martin J.-J., RA Van Broeckhoven C.; RT "Digenic progressive external ophthalmoplegia in a sporadic patient: RT recessive mutations in POLG and C10orf2/Twinkle."; RL Hum. Mutat. 22:175-176(2003). RN [26] RP VARIANTS PEO TRP-303 AND GLN-334. RX PubMed=12707443; DOI=10.1212/01.wnl.0000056088.09408.3c; RA Agostino A., Valletta L., Chinnery P.F., Ferrari G., Carrara F., RA Taylor R.W., Schaefer A.M., Turnbull D.M., Tiranti V., Zeviani M.; RT "Mutations of ANT1, Twinkle, and POLG1 in sporadic progressive external RT ophthalmoplegia (PEO)."; RL Neurology 60:1354-1356(2003). RN [27] RP VARIANT PEOA3 THR-319. RX PubMed=12921794; DOI=10.1016/s0960-8966(03)00071-3; RA Deschauer M., Kiefer R., Blakely E.L., He L., Zierz S., Turnbull D.M., RA Taylor R.W.; RT "A novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia."; RL Neuromuscul. Disord. 13:568-572(2003). RN [28] RP VARIANT MTDPS7 CYS-508. RX PubMed=16135556; DOI=10.1093/hmg/ddi328; RA Nikali K., Suomalainen A., Saharinen J., Kuokkanen M., Spelbrink J.N., RA Loennqvist T., Peltonen L.; RT "Infantile onset spinocerebellar ataxia is caused by recessive mutations in RT mitochondrial proteins Twinkle and Twinky."; RL Hum. Mol. Genet. 14:2981-2990(2005). RN [29] RP VARIANT PEOA3 GLU-319. RX PubMed=15668446; DOI=10.1212/01.wnl.0000149767.51152.83; RA Hudson G., Deschauer M., Busse K., Zierz S., Chinnery P.F.; RT "Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable RT germline mosaicism."; RL Neurology 64:371-373(2005). RN [30] RP VARIANT PEOA3 GLN-374, AND VARIANT ILE-368. RX PubMed=16639411; DOI=10.1038/sj.ejhg.5201627; RA Naiemi M., Bannwarth S., Procaccio V., Pouget J., Desnuelle C., RA Pellissier J.-F., Roetig A., Munnich A., Calvas P., Richelme C., RA Jonveaux P., Castelnovo G., Simon M., Clanet M., Wallace D., RA Paquis-Flucklinger V.; RT "Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple RT deletions or depletion of mitochondrial DNA by a dHPLC-based assay."; RL Eur. J. Hum. Genet. 14:917-922(2006). RN [31] RP VARIANT MTDPS7 ILE-457, AND CHARACTERIZATION OF VARIANT MTDPS7 ILE-457. RX PubMed=17722119; DOI=10.1002/ana.21207; RA Sarzi E., Goffart S., Serre V., Chretien D., Slama A., Munnich A., RA Spelbrink J.N., Roetig A.; RT "Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA RT depletion."; RL Ann. Neurol. 62:579-587(2007). RN [32] RP VARIANTS MTDPS7 THR-318 AND CYS-508. RX PubMed=17921179; DOI=10.1093/brain/awm242; RA Hakonen A.H., Isohanni P., Paetau A., Herva R., Suomalainen A., RA Lonnqvist T.; RT "Recessive Twinkle mutations in early onset encephalopathy with mtDNA RT depletion."; RL Brain 130:3032-3040(2007). RN [33] RP VARIANT PEOA3 PRO-357. RX PubMed=17614277; DOI=10.1016/j.nmd.2007.05.006; RA Rivera H., Blazquez A., Carretero J., Alvarez-Cermeno J.C., Campos Y., RA Cabello A., Gonzalez-Vioque E., Borstein B., Garesse R., Arenas J., RA Martin M.A.; RT "Mild ocular myopathy associated with a novel mutation in mitochondrial RT twinkle helicase."; RL Neuromuscul. Disord. 17:677-680(2007). RN [34] RP VARIANTS PEOA3 TRP-303; SER-315; PRO-334; ASN-426; SER-474; ILE-478 AND RP LYS-479. RX PubMed=18575922; DOI=10.1007/s00415-008-0926-3; RA Virgilio R., Ronchi D., Hadjigeorgiou G.M., Bordoni A., Saladino F., RA Moggio M., Adobbati L., Kafetsouli D., Tsironi E., Previtali S., RA Papadimitriou A., Bresolin N., Comi G.P.; RT "Novel Twinkle (PEO1) gene mutations in Mendelian progressive external RT ophthalmoplegia."; RL J. Neurol. 255:1384-1391(2008). RN [35] RP VARIANT PEOA3 LEU-370. RX PubMed=18396044; DOI=10.1016/j.nmd.2007.10.007; RA Jeppesen T.D., Schwartz M., Colding-Jorgensen E., Krag T., Hauerslev S., RA Vissing J.; RT "Phenotype and clinical course in a family with a new de novo Twinkle gene RT mutation."; RL Neuromuscul. Disord. 18:306-309(2008). RN [36] RP VARIANT PEOA3 GLN-303. RX PubMed=19353676; DOI=10.1002/ajmg.a.32731; RA Van Hove J.L., Cunningham V., Rice C., Ringel S.P., Zhang Q., Chou P.C., RA Truong C.K., Wong L.J.; RT "Finding twinkle in the eyes of a 71-year-old lady: a case report and RT review of the genotypic and phenotypic spectrum of TWINKLE-related dominant RT disease."; RL Am. J. Med. Genet. A 149:861-867(2009). RN [37] RP VARIANT PEOA3 TRP-303. RX PubMed=19428252; DOI=10.1016/j.nmd.2009.04.008; RA Negro R., Zoccolella S., Dell'aglio R., Amati A., Artuso L., Bisceglia L., RA Lavolpe V., Papa S., Serlenga L., Petruzzella V.; RT "Molecular analysis in a family presenting with a mild form of late-onset RT autosomal dominant chronic progressive external ophthalmoplegia."; RL Neuromuscul. Disord. 19:423-426(2009). RN [38] RP VARIANT MTDPS7 GLY-360. RX PubMed=19853444; DOI=10.1016/j.nmd.2009.10.002; RA Bohlega S., Van Goethem G., Al Semari A., Lofgren A., Al Hamed M., RA Van Broeckhoven C., Kambouris M.; RT "Novel Twinkle gene mutation in autosomal dominant progressive external RT ophthalmoplegia and multisystem failure."; RL Neuromuscul. Disord. 19:845-848(2009). RN [39] RP VARIANTS PEOA3 GLN-303; TRP-303; GLN-334; PRO-354; PRO-357; THR-359; RP PRO-362; LEU-363; CYS-370; GLN-374; PRO-381; HIS-458; PRO-460; ASP-475 AND RP LYS-479. RX PubMed=20479361; DOI=10.1212/wnl.0b013e3181df099f; RA Fratter C., Gorman G.S., Stewart J.D., Buddles M., Smith C., Evans J., RA Seller A., Poulton J., Roberts M., Hanna M.G., Rahman S., Omer S.E., RA Klopstock T., Schoser B., Kornblum C., Czermin B., Lecky B., Blakely E.L., RA Craig K., Chinnery P.F., Turnbull D.M., Horvath R., Taylor R.W.; RT "The clinical, histochemical, and molecular spectrum of PEO1 (Twinkle)- RT linked adPEO."; RL Neurology 74:1619-1626(2010). RN [40] RP VARIANT PEOA3 GLN-374. RX PubMed=20880070; DOI=10.1111/j.1468-1331.2010.03171.x; RA Martin-Negrier M.L., Sole G., Jardel C., Vital C., Ferrer X., Vital A.; RT "TWINKLE gene mutation: report of a French family with an autosomal RT dominant progressive external ophthalmoplegia and literature review."; RL Eur. J. Neurol. 18:436-441(2011). RN [41] RP VARIANT MTDPS7 VAL-456. RX PubMed=22353293; DOI=10.1016/j.pediatrneurol.2011.12.006; RA Dundar H., Ozgul R.K., Yalnizoglu D., Erdem S., Oguz K.K., Tuncel D., RA Temucin C.M., Dursun A.; RT "Identification of a novel Twinkle mutation in a family with infantile RT onset spinocerebellar ataxia by whole exome sequencing."; RL Pediatr. Neurol. 46:172-177(2012). RN [42] RP INVOLVEMENT IN PRLTS5, AND VARIANTS PRLTS5 HIS-391; GLY-441; ILE-507 AND RP SER-585. RX PubMed=25355836; DOI=10.1212/wnl.0000000000001036; RA Morino H., Pierce S.B., Matsuda Y., Walsh T., Ohsawa R., Newby M., RA Hiraki-Kamon K., Kuramochi M., Lee M.K., Klevit R.E., Martin A., RA Maruyama H., King M.C., Kawakami H.; RT "Mutations in Twinkle primase-helicase cause Perrault syndrome with RT neurologic features."; RL Neurology 83:2054-2061(2014). CC -!- FUNCTION: [Isoform 1]: Mitochondrial helicase involved in mtDNA CC replication and repair (PubMed:12975372, PubMed:15167897, CC PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, CC PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair CC (PubMed:27226550). Has DNA strand separation activity needed to form a CC processive replication fork for leading strand synthesis which is CC catalyzed by the formation of a replisome complex with POLG and mtSDB CC (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, CC PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA CC substrates with pre-existing 5'-and 3'- single-stranded tails but is CC also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897, CC PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). CC Can dissociate the invading strand of immobile or mobile D-loop DNA CC structures irrespective of the single strand polarity of the third CC strand (PubMed:27226550). In addition to its DNA strand separation CC activity, also has DNA strand annealing, DNA strand-exchange and DNA CC branch migration activities (PubMed:22383523, PubMed:26887820, CC PubMed:27226550). {ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:15167897, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:26887820, ECO:0000269|PubMed:27226550}. CC -!- FUNCTION: [Isoform 2]: Lack DNA unwinding and ATP hydrolysis activities CC (PubMed:18039713). Does not bind single-stranded or double-stranded DNA CC (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=ATP + H2O = ADP + phosphate + H(+); Xref=Rhea:RHEA:13065, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=5.6.2.3; CC Evidence={ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:17324440, CC ECO:0000269|PubMed:18039713, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949, CC ECO:0000269|PubMed:27226550, ECO:0000269|PubMed:35914129}; CC -!- CATALYTIC ACTIVITY: [Isoform 1]: CC Reaction=Couples ATP hydrolysis with the unwinding of duplex DNA at the CC replication fork by translocating in the 5'-3' direction.; CC EC=5.6.2.3; Evidence={ECO:0000269|PubMed:12975372, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:27226550, CC ECO:0000269|PubMed:35914129}; CC -!- ACTIVITY REGULATION: [Isoform 1]: Strand annealing activity is CC inhibited by 150 mM NaCl (in vitro). {ECO:0000269|PubMed:22383523}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: [Isoform 1]: CC Kinetic parameters: CC KM=1.7 mM for UTP (using ssM13mp18 as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.6 mM for UTP (using ssDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=1.4 mM for UTP (using forked dsDNA as DNA substrate) CC {ECO:0000269|PubMed:22383523}; CC KM=3.4 mM for UTP (using no DNA as substrate) CC {ECO:0000269|PubMed:22383523}; CC -!- SUBUNIT: Interacts with LONP1. {ECO:0000269|PubMed:14739292}. CC -!- SUBUNIT: [Isoform 1]: Homohexamer (via C-terminus), which assembles in CC a ring-like structure (PubMed:17324440, PubMed:18039713, CC PubMed:18971204, PubMed:22383523, PubMed:25824949, PubMed:30496414). CC Homoheptamer, which assembles in a ring-like structure CC (PubMed:25824949, PubMed:30496414, PubMed:35914129). Homooctamer, which CC assembles in a ring-like structure (PubMed:35914129). Oligomers may CC sequentially eject two monomers (octamer>heptamer>hexamer) upon DNA CC binding (PubMed:35914129). Oligomerization is Mg(2+), nucleotide and CC DNA-independent, however, Mg(2+) and nucleotide stabilize the CC homohexameric form (PubMed:18039713). Interacts with POLG in vitro CC (PubMed:15167897). {ECO:0000269|PubMed:15167897, CC ECO:0000269|PubMed:17324440, ECO:0000269|PubMed:18039713, CC ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:22383523, CC ECO:0000269|PubMed:25824949, ECO:0000269|PubMed:30496414, CC ECO:0000269|PubMed:35914129}. CC -!- SUBUNIT: [Isoform 2]: Monomer (PubMed:18039713). Does not form CC oligomers (PubMed:18039713). {ECO:0000269|PubMed:18039713}. CC -!- INTERACTION: CC Q96RR1; Q08380: LGALS3BP; NbExp=2; IntAct=EBI-716458, EBI-354956; CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix, mitochondrion nucleoid CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:18971204}. CC Mitochondrion inner membrane {ECO:0000303|PubMed:34950192}; Peripheral CC membrane protein {ECO:0000269|PubMed:34950192}. Note=Colocalizes with CC mtDNA in mitochondrial nucleoids, a nucleoproteins complex consisting CC of a number of copies of proteins associated with mtDNA, probably CC involved in mtDNA maintenance and expression (PubMed:11431692). CC Associates with phospholipid membranes via electrostatic binding (By CC similarity). Preferentially associates with membranes enriched with CC cardiolipin, a lipid abundant in the mitochondrial inner membrane CC (PubMed:34950192). ATPase and helicase activity is enhanced by binding CC to lipid membranes (PubMed:34950192). {ECO:0000250|UniProtKB:Q9VL76, CC ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:34950192}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q96RR1-1; Sequence=Displayed; CC Name=2; Synonyms=Twinky; CC IsoId=Q96RR1-2; Sequence=VSP_015960, VSP_015961; CC Name=3; CC IsoId=Q96RR1-3; Sequence=VSP_015959; CC -!- TISSUE SPECIFICITY: High relative levels in skeletal muscle, testis and CC pancreas. Lower levels of expression in the heart, brain, placenta, CC lung, liver, kidney, spleen, thymus, prostate, ovary, small intestine, CC colon and leukocytes. Expression is coregulated with MRPL43. CC {ECO:0000269|PubMed:11431692, ECO:0000269|PubMed:15509589}. CC -!- DOMAIN: N-terminus enhances protein stability and hexamer formation, CC which is important for DNA binding, and is required for DNA helicase CC activity and, ultimately, for mtDNA replisome processivity. CC {ECO:0000269|PubMed:18039713}. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 3 (PEOA3) [MIM:609286]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:11431692, CC ECO:0000269|PubMed:12163192, ECO:0000269|PubMed:12921794, CC ECO:0000269|PubMed:15668446, ECO:0000269|PubMed:16639411, CC ECO:0000269|PubMed:17614277, ECO:0000269|PubMed:18396044, CC ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19353676, CC ECO:0000269|PubMed:19428252, ECO:0000269|PubMed:20479361, CC ECO:0000269|PubMed:20880070}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 7 (MTDPS7) [MIM:271245]: CC A severe disease associated with mitochondrial dysfunction. Some CC patients are affected by progressive atrophy of the cerebellum, brain CC stem, the spinal cord, and sensory axonal neuropathy. Clinical features CC include hypotonia, athetosis, ataxia, ophthalmoplegia, sensorineural CC hearing deficit, sensory axonal neuropathy, epileptic encephalopathy CC and female hypogonadism. In some individuals liver dysfunction and CC multi-organ failure is present. {ECO:0000269|PubMed:16135556, CC ECO:0000269|PubMed:17722119, ECO:0000269|PubMed:17921179, CC ECO:0000269|PubMed:19853444, ECO:0000269|PubMed:22353293}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Perrault syndrome 5 (PRLTS5) [MIM:616138]: A form of Perrault CC syndrome, a sex-influenced disorder characterized by sensorineural CC deafness in both males and females, and ovarian dysgenesis in females. CC Affected females have primary amenorrhea, streak gonads, and CC infertility, whereas affected males show normal pubertal development CC and are fertile. PRLTS5 is an autosomal recessive form characterized by CC progressive ataxia, axonal neuropathy, hyporeflexia and abnormal eye CC movements, in addition to deafness and ovarian dysgenesis. CC {ECO:0000269|PubMed:25355836}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- CAUTION: The N-terminus contains a putative primase-like domain; CC however the absence of the zinc binding domain and other motifs CC important for catalysis suggests that TWNK lacks primase activity. CC {ECO:0000305|PubMed:25824949}. CC -!- CAUTION: In vitro, can catalyze the hydrolysis of different nucleotide CC triphosphate (NTP) substrates with different efficiency. CC {ECO:0000269|PubMed:12975372, ECO:0000269|PubMed:18971204, CC ECO:0000269|PubMed:22383523, ECO:0000269|PubMed:25824949}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF292004; AAK69558.1; -; mRNA. DR EMBL; AF292005; AAK69559.1; -; mRNA. DR EMBL; BX640829; CAE45905.1; -; mRNA. DR EMBL; AL133215; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; EU543650; ACB21043.1; -; Genomic_DNA. DR EMBL; CH471066; EAW49794.1; -; Genomic_DNA. DR EMBL; BC013349; AAH13349.1; -; mRNA. DR CCDS; CCDS53570.1; -. [Q96RR1-2] DR CCDS; CCDS7506.1; -. [Q96RR1-1] DR RefSeq; NP_001157284.1; NM_001163812.2. [Q96RR1-2] DR RefSeq; NP_068602.2; NM_021830.4. [Q96RR1-1] DR PDB; 7T8B; EM; 3.80 A; A/B/C/D/E/F/G/H=1-684. DR PDB; 7T8C; EM; 4.50 A; A/B/C/D/E/F/G=1-684. DR PDBsum; 7T8B; -. DR PDBsum; 7T8C; -. DR AlphaFoldDB; Q96RR1; -. DR EMDB; EMD-25743; -. DR EMDB; EMD-25744; -. DR SMR; Q96RR1; -. DR BioGRID; 121166; 148. DR FunCoup; Q96RR1; 1571. DR IntAct; Q96RR1; 83. DR MINT; Q96RR1; -. DR STRING; 9606.ENSP00000309595; -. DR GlyGen; Q96RR1; 1 site. DR iPTMnet; Q96RR1; -. DR PhosphoSitePlus; Q96RR1; -. DR BioMuta; TWNK; -. DR DMDM; 74752111; -. DR jPOST; Q96RR1; -. DR MassIVE; Q96RR1; -. DR PaxDb; 9606-ENSP00000309595; -. DR PeptideAtlas; Q96RR1; -. DR ProteomicsDB; 78006; -. [Q96RR1-1] DR ProteomicsDB; 78007; -. [Q96RR1-2] DR ProteomicsDB; 78008; -. [Q96RR1-3] DR Pumba; Q96RR1; -. DR Antibodypedia; 1261; 217 antibodies from 25 providers. DR DNASU; 56652; -. DR Ensembl; ENST00000311916.8; ENSP00000309595.2; ENSG00000107815.10. [Q96RR1-1] DR Ensembl; ENST00000370228.2; ENSP00000359248.1; ENSG00000107815.10. [Q96RR1-2] DR Ensembl; ENST00000643860.1; ENSP00000494389.1; ENSG00000107815.10. [Q96RR1-3] DR GeneID; 56652; -. DR KEGG; hsa:56652; -. DR MANE-Select; ENST00000311916.8; ENSP00000309595.2; NM_021830.5; NP_068602.2. DR UCSC; uc001ksf.3; human. [Q96RR1-1] DR AGR; HGNC:1160; -. DR ClinPGx; PA162377675; -. DR CTD; 56652; -. DR DisGeNET; 56652; -. DR GeneCards; TWNK; -. DR HGNC; HGNC:1160; TWNK. DR HPA; ENSG00000107815; Low tissue specificity. DR MalaCards; TWNK; -. DR MIM; 271245; phenotype. DR MIM; 606075; gene. DR MIM; 609286; phenotype. DR MIM; 616138; phenotype. DR OpenTargets; ENSG00000107815; -. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 1186; Infantile-onset spinocerebellar ataxia. DR Orphanet; 363534; Mitochondrial DNA depletion syndrome, hepatocerebrorenal form. DR Orphanet; 642945; Perrault syndrome type 1. DR Orphanet; 642976; Perrault syndrome type 2. DR Orphanet; 70595; Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. DR VEuPathDB; HostDB:ENSG00000107815; -. DR eggNOG; KOG2373; Eukaryota. DR GeneTree; ENSGT00390000004495; -. DR HOGENOM; CLU_012336_1_0_1; -. DR InParanoid; Q96RR1; -. DR OMA; GIRWSRF; -. DR OrthoDB; 275278at2759; -. DR PAN-GO; Q96RR1; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q96RR1; -. DR BRENDA; 3.6.4.12; 2681. DR PathwayCommons; Q96RR1; -. DR Reactome; R-HSA-2151201; Transcriptional activation of mitochondrial biogenesis. DR Reactome; R-HSA-9837999; Mitochondrial protein degradation. DR Reactome; R-HSA-9913635; Strand-asynchronous mitochondrial DNA replication. DR SignaLink; Q96RR1; -. DR Agora; ENSG00000107815; -. DR BioGRID-ORCS; 56652; 354 hits in 1149 CRISPR screens. DR ChiTaRS; TWNK; human. DR GeneWiki; PEO1; -. DR GenomeRNAi; 56652; -. DR Pharos; Q96RR1; Tbio. DR PRO; PR:Q96RR1; -. DR Proteomes; UP000005640; Chromosome 10. DR RNAct; Q96RR1; protein. DR Bgee; ENSG00000107815; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 139 other cell types or tissues. DR ExpressionAtlas; Q96RR1; baseline and differential. DR GO; GO:0000262; C:mitochondrial chromosome; IDA:FlyBase. DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome. DR GO; GO:0042645; C:mitochondrial nucleoid; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; HTP:FlyBase. DR GO; GO:0043139; F:5'-3' DNA helicase activity; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0016887; F:ATP hydrolysis activity; IDA:FlyBase. DR GO; GO:0003678; F:DNA helicase activity; IBA:GO_Central. DR GO; GO:0042802; F:identical protein binding; IPI:UniProtKB. DR GO; GO:0008289; F:lipid binding; IDA:FlyBase. DR GO; GO:0002020; F:protease binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; IDA:FlyBase. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:UniProtKB. DR GO; GO:0006390; P:mitochondrial transcription; IMP:UniProtKB. DR GO; GO:0034214; P:protein hexamerization; IDA:UniProtKB. DR CDD; cd01029; TOPRIM_primases; 1. DR CDD; cd01122; Twinkle_C; 1. DR FunFam; 3.40.1360.10:FF:000008; Mitochondrial helicase twinkle; 1. DR FunFam; 3.40.50.300:FF:000845; Mitochondrial helicase twinkle; 1. DR Gene3D; 3.40.1360.10; -; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR007694; DNA_helicase_DnaB-like_C. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR034154; TOPRIM_DnaG/twinkle. DR InterPro; IPR027032; Twinkle-like. DR PANTHER; PTHR12873; T7-LIKE MITOCHONDRIAL DNA HELICASE; 1. DR PANTHER; PTHR12873:SF0; TWINKLE MTDNA HELICASE; 1. DR Pfam; PF13481; AAA_25; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR PROSITE; PS51199; SF4_HELICASE; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Deafness; Disease variant; KW DNA replication; Helicase; Hydrolase; Isomerase; Lipid-binding; Membrane; KW Mitochondrion; Mitochondrion inner membrane; Mitochondrion nucleoid; KW Neurodegeneration; Neuropathy; Nucleotide-binding; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome; Transit peptide. FT TRANSIT 1..31 FT /note="Mitochondrion" FT /evidence="ECO:0000255" FT CHAIN 32..684 FT /note="Twinkle mtDNA helicase" FT /id="PRO_0000042640" FT DOMAIN 384..635 FT /note="SF4 helicase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT REGION 1..121 FT /note="Contributes to single strand DNA binding activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 54..214 FT /note="N-terminal region (NTR)" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 121..372 FT /note="Required for hexamers formation and DNA helicase FT activity" FT /evidence="ECO:0000269|PubMed:18039713" FT REGION 215..335 FT /note="Primase-like domain" FT /evidence="ECO:0000269|PubMed:35914129" FT REGION 405..590 FT /note="Maybe required for stable oligomeric structure" FT /evidence="ECO:0000269|PubMed:17324440" FT REGION 637..684 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 640..684 FT /note="Might negatively regulate ATPase activity" FT /evidence="ECO:0000269|PubMed:17324440" FT COMPBIAS 659..677 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 415..422 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00596" FT VAR_SEQ 532..684 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_015959" FT VAR_SEQ 579..582 FT /note="ASQE -> VSGL (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015960" FT VAR_SEQ 583..684 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11431692, FT ECO:0000303|PubMed:15489334" FT /id="VSP_015961" FT VARIANT 303 FT /note="R -> Q (in PEOA3; dbSNP:rs137852956)" FT /evidence="ECO:0000269|PubMed:19353676, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065102" FT VARIANT 303 FT /note="R -> W (in PEOA3; also detected in a case showing FT digenic inheritance; dbSNP:rs1159929268)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:18575922, ECO:0000269|PubMed:19428252, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023647" FT VARIANT 315 FT /note="W -> L (in PEOA3; reduced single-strand DNA binding; FT increased heptamer oligomerization; increased stability of FT the closed or 'compacted' conformation; dbSNP:rs111033575)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:30496414, ECO:0000269|PubMed:35914129" FT /id="VAR_023648" FT VARIANT 315 FT /note="W -> S (in PEOA3; reduces helicase activity; reduced FT single-strand DNA binding)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:18971204" FT /id="VAR_065103" FT VARIANT 318 FT /note="A -> T (in MTDPS7; dbSNP:rs80356542)" FT /evidence="ECO:0000269|PubMed:17921179" FT /id="VAR_065104" FT VARIANT 319 FT /note="K -> E (in PEOA3; the phenotype highly overlaps with FT sensory ataxic neuropathy dysarthria and ophthalmoparesis; FT reduces helicase activity and single-strand DNA binding; FT dbSNP:rs80356543)" FT /evidence="ECO:0000269|PubMed:15668446, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023649" FT VARIANT 319 FT /note="K -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:12921794" FT /id="VAR_023650" FT VARIANT 334 FT /note="R -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065105" FT VARIANT 334 FT /note="R -> Q (in PEO; sporadic case; the patient also FT carries the S-848 mutation in the POLG gene suggesting FT digenic inheritance; retains hexamer and heptamer FT formation; dbSNP:rs28937887)" FT /evidence="ECO:0000269|PubMed:12707443, FT ECO:0000269|PubMed:12872260, ECO:0000269|PubMed:20479361, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023651" FT VARIANT 335 FT /note="P -> L (in PEOA3; displays unusual oligomeric FT forms)" FT /evidence="ECO:0000269|PubMed:12163192, FT ECO:0000269|PubMed:30496414" FT /id="VAR_023652" FT VARIANT 348 FT /note="G -> R (in dbSNP:rs62626271)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062268" FT VARIANT 354 FT /note="R -> P (in PEOA3; dbSNP:rs111033576)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361" FT /id="VAR_023653" FT VARIANT 357 FT /note="R -> P (in PEOA3; dbSNP:rs758026634)" FT /evidence="ECO:0000269|PubMed:17614277, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065106" FT VARIANT 359 FT /note="A -> T (in PEOA3; reduces helicase activity; FT dbSNP:rs111033573)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:20479361" FT /id="VAR_023654" FT VARIANT 360 FT /note="L -> G (in MTDPS7; patients manifest multi-organ FT failure; requires 2 nucleotide substitutions)" FT /evidence="ECO:0000269|PubMed:19853444" FT /id="VAR_065107" FT VARIANT 362 FT /note="A -> P (in PEOA3; dbSNP:rs1554887075)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065108" FT VARIANT 363 FT /note="W -> L (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065109" FT VARIANT 367 FT /note="I -> T (in PEOA3)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023655" FT VARIANT 368 FT /note="V -> I (in dbSNP:rs17113613)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:12557300, ECO:0000269|PubMed:16639411, FT ECO:0000269|Ref.4" FT /id="VAR_023656" FT VARIANT 369 FT /note="S -> P (in PEOA3; reduces helicase activity; FT increases single strand DNA affinity; reduces closed-ring FT quaternary structure formation)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204, ECO:0000269|PubMed:30496414" FT /id="VAR_023657" FT VARIANT 369 FT /note="S -> Y (in PEOA3; dbSNP:rs111033579)" FT /evidence="ECO:0000269|PubMed:12163192" FT /id="VAR_023658" FT VARIANT 370 FT /note="F -> C (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065110" FT VARIANT 370 FT /note="F -> L (in PEOA3; dbSNP:rs863223920)" FT /evidence="ECO:0000269|PubMed:18396044" FT /id="VAR_065111" FT VARIANT 374 FT /note="R -> Q (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs1554887097)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:16639411, ECO:0000269|PubMed:18971204, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:20880070" FT /id="VAR_023659" FT VARIANT 381 FT /note="L -> P (in PEOA3; reduces closed-ring quaternary FT structure formation; dbSNP:rs111033577)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:20479361, ECO:0000269|PubMed:30496414" FT /id="VAR_023660" FT VARIANT 391 FT /note="R -> H (in PRLTS5; dbSNP:rs556445621)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072657" FT VARIANT 426 FT /note="S -> N (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065112" FT VARIANT 427 FT /note="E -> G (in dbSNP:rs11542126)" FT /id="VAR_051267" FT VARIANT 441 FT /note="W -> G (in PRLTS5; dbSNP:rs672601361)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072658" FT VARIANT 456 FT /note="L -> V (in MTDPS7; infantile spinocerebellar ataxia FT phenotype; dbSNP:rs386834145)" FT /evidence="ECO:0000269|PubMed:22353293" FT /id="VAR_067722" FT VARIANT 457 FT /note="T -> I (in MTDPS7; affects helicase activity; FT dbSNP:rs80356544)" FT /evidence="ECO:0000269|PubMed:17722119" FT /id="VAR_039045" FT VARIANT 458 FT /note="Q -> H (in PEOA3; dbSNP:rs1554887213)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065113" FT VARIANT 460 FT /note="A -> P (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065114" FT VARIANT 474 FT /note="W -> C (in PEOA3; reduces helicase activity and FT alters nucleoid structure; dbSNP:rs111033574)" FT /evidence="ECO:0000269|PubMed:11431692, FT ECO:0000269|PubMed:18971204" FT /id="VAR_023661" FT VARIANT 474 FT /note="W -> S (in PEOA3; dbSNP:rs11542127)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065115" FT VARIANT 475 FT /note="A -> D (in PEOA3)" FT /evidence="ECO:0000269|PubMed:20479361" FT /id="VAR_065116" FT VARIANT 475 FT /note="A -> P (in PEOA3; dbSNP:rs111033572)" FT /evidence="ECO:0000269|PubMed:11431692" FT /id="VAR_023662" FT VARIANT 478 FT /note="F -> I (in PEOA3)" FT /evidence="ECO:0000269|PubMed:18575922" FT /id="VAR_065117" FT VARIANT 479 FT /note="E -> K (in PEOA3; dbSNP:rs1085307937)" FT /evidence="ECO:0000269|PubMed:18575922, FT ECO:0000269|PubMed:20479361" FT /id="VAR_065118" FT VARIANT 507 FT /note="V -> I (in PRLTS5; dbSNP:rs369588002)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072659" FT VARIANT 508 FT /note="Y -> C (in MTDPS7; dbSNP:rs80356540)" FT /evidence="ECO:0000269|PubMed:16135556, FT ECO:0000269|PubMed:17921179" FT /id="VAR_043797" FT VARIANT 585 FT /note="N -> S (in PRLTS5; dbSNP:rs672601360)" FT /evidence="ECO:0000269|PubMed:25355836" FT /id="VAR_072660" FT VARIANT 634 FT /note="N -> K (in dbSNP:rs62626293)" FT /evidence="ECO:0000269|Ref.4" FT /id="VAR_062269" FT MUTAGEN 421 FT /note="K->A: Loss of helicase activity on 5'-tailed FT substrate." FT /evidence="ECO:0000269|PubMed:22383523" FT CONFLICT 351 FT /note="N -> D (in Ref. 3; CAE45905)" FT /evidence="ECO:0000305" SQ SEQUENCE 684 AA; 77154 MW; 58186043888234DA CRC64; MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATEI RQYLRGHGIP FQDGHSCLRA LSPFAESSQL KGQTGVTTSF SLFIDKTTGH FLCMTSLAEG SWEDFQASVE GRGDGAREGF LLSKAPEFED SEEVRRIWNR AIPLWELPDQ EEVQLADTMF GLTKVTDDTL KRFSVRYLRP ARSLVFPWFS PGGSGLRGLK LLEAKCQGDG VSYEETTIPR PSAYHNLFGL PLISRRDAEV VLTSRELDSL ALNQSTGLPT LTLPRGTTCL PPALLPYLEQ FRRIVFWLGD DLRSWEAAKL FARKLNPKRC FLVRPGDQQP RPLEALNGGF NLSRILRTAL PAWHKSIVSF RQLREEVLGE LSNVEQAAGL RWSRFPDLNR ILKGHRKGEL TVFTGPTGSG KTTFISEYAL DLCSQGVNTL WGSFEISNVR LARVMLTQFA EGRLEDQLDK YDHWADRFED LPLYFMTFHG QQSIRTVIDT MQHAVYVYDI CHVIIDNLQF MMGHEQLSTD RIAAQDYIIG VFRKFATDNN CHVTLVIHPR KEDDDKELQT ASIFGSAKAS QEADNVLILQ DRKLVTGPGK RYLQVSKNRF DGDVGVFPLE FNKNSLTFSI PPKNKARLKK IKDDTGPVAK KPSSGKKGAT TQNSEICSGQ APTPDQPDTS KRSK // ID RIR2B_HUMAN Reviewed; 351 AA. AC Q7LG56; B4E2N4; Q17R22; Q75PQ6; Q75PQ7; Q75PY8; Q75PY9; Q86YE3; Q9NPD6; AC Q9NTD8; Q9NUW3; DT 21-MAR-2006, integrated into UniProtKB/Swiss-Prot. DT 05-JUL-2004, sequence version 1. DT 28-JAN-2026, entry version 197. DE RecName: Full=Ribonucleoside-diphosphate reductase subunit M2 B; DE EC=1.17.4.1; DE AltName: Full=TP53-inducible ribonucleotide reductase M2 B; DE AltName: Full=p53-inducible ribonucleotide reductase small subunit 2-like protein; DE Short=p53R2; GN Name=RRM2B; Synonyms=P53R2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), FUNCTION, AND RP INDUCTION. RX PubMed=10716435; DOI=10.1038/35003506; RA Tanaka H., Arakawa H., Yamaguchi T., Shiraishi K., Fukuda S., Matsui K., RA Takei Y., Nakamura Y.; RT "A ribonucleotide reductase gene involved in a p53-dependent cell-cycle RT checkpoint for DNA damage."; RL Nature 404:42-49(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5). RA Ugai H., Yokoyama K.K.; RT "Homo sapiens p53-inducible ribonucleotide reductase small subunit 2 RT splicing variants."; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE SEQUENCE RP [LARGE SCALE MRNA] OF 1-351 (ISOFORM 6). RC TISSUE=Placenta, and Trachea; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Amygdala; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16421571; DOI=10.1038/nature04406; RA Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., RA Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., RA Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., RA Asakawa T., Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., RA Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, RA Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., RA Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., RA Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., RA Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., RA O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., RA Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., RA Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., RA Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., RA Platzer M., Shimizu N., Lander E.S.; RT "DNA sequence and analysis of human chromosome 8."; RL Nature 439:331-335(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP FUNCTION, AND SUBUNIT. RX PubMed=11517226; DOI=10.1074/jbc.m106088200; RA Guittet O., Haakansson P., Voevodskaya N., Fridd S., Graeslund A., RA Arakawa H., Nakamura Y., Thelander L.; RT "Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro RT with the R1 protein, which is expressed both in resting cells in response RT to DNA damage and in proliferating cells."; RL J. Biol. Chem. 276:40647-40651(2001). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, AND VARIANT LEU-115. RX PubMed=11719458; RA Yamaguchi T., Matsuda K., Sagiya Y., Iwadate M., Fujino M.A., Nakamura Y., RA Arakawa H.; RT "p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle RT checkpoint."; RL Cancer Res. 61:8256-8262(2001). RN [11] RP SUBCELLULAR LOCATION, AND INTERACTION WITH TP53 AND RRM1. RX PubMed=12615712; RA Xue L., Zhou B., Liu X., Qiu W., Jin Z., Yen Y.; RT "Wild-type p53 regulates human ribonucleotide reductase by protein-protein RT interaction with p53R2 as well as hRRM2 subunits."; RL Cancer Res. 63:980-986(2003). RN [12] RP TISSUE SPECIFICITY. RX PubMed=14583450; RA Zhou B., Liu X., Mo X., Xue L., Darwish D., Qiu W., Shih J., Hwu E.B., RA Luh F., Yen Y.; RT "The human ribonucleotide reductase subunit hRRM2 complements p53R2 in RT response to UV-induced DNA repair in cells with mutant p53."; RL Cancer Res. 63:6583-6594(2003). RN [13] RP CATALYTIC ACTIVITY, AND SUBUNIT. RX PubMed=16376858; DOI=10.1016/j.bbrc.2005.12.019; RA Qiu W., Zhou B., Darwish D., Shao J., Yen Y.; RT "Characterization of enzymatic properties of human ribonucleotide reductase RT holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits."; RL Biochem. Biophys. Res. Commun. 340:428-434(2006). RN [14] RP INVOLVEMENT IN PEOA5. RX PubMed=19664747; DOI=10.1016/j.ajhg.2009.07.009; RA Tyynismaa H., Ylikallio E., Patel M., Molnar M.J., Haller R.G., RA Suomalainen A.; RT "A heterozygous truncating mutation in RRM2B causes autosomal-dominant RT progressive external ophthalmoplegia with multiple mtDNA deletions."; RL Am. J. Hum. Genet. 85:290-295(2009). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [16] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH IRON IONS, AND RP COFACTOR. RX PubMed=19728742; DOI=10.1021/bi9001425; RA Smith P., Zhou B., Ho N., Yuan Y.C., Su L., Tsai S.C., Yen Y.; RT "2.6 A X-ray crystal structure of human p53R2, a p53-inducible RT ribonucleotide reductase."; RL Biochemistry 48:11134-11141(2009). RN [17] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 20-322 IN COMPLEX WITH IRON IONS. RG Structural genomics consortium (SGC); RT "Human ribonucleotide reductase, subunit M2 B."; RL Submitted (FEB-2009) to the PDB data bank. RN [18] RP VARIANTS MTDPS8A ARG-64; GLU-85 DEL; GLY-194; LYS-194 AND PHE-236. RX PubMed=17486094; DOI=10.1038/ng2040; RA Bourdon A., Minai L., Serre V., Jais J.-P., Sarzi E., Aubert S., RA Chretien D., de Lonlay P., Paquis-Flucklinger V., Arakawa H., Nakamura Y., RA Munnich A., Roetig A.; RT "Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase RT (p53R2), causes severe mitochondrial DNA depletion."; RL Nat. Genet. 39:776-780(2007). RN [19] RP VARIANTS MTDPS8A SER-224; ILE-282 AND VAL-317. RX PubMed=18504129; DOI=10.1016/j.nmd.2008.04.006; RA Bornstein B., Area E., Flanigan K.M., Ganesh J., Jayakar P., Swoboda K.J., RA Coku J., Naini A., Shanske S., Tanji K., Hirano M., DiMauro S.; RT "Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene."; RL Neuromuscul. Disord. 18:453-459(2008). RN [20] RP VARIANTS MTDPS8B HIS-110 AND HIS-121. RX PubMed=19667227; DOI=10.1001/archneurol.2009.139; RA Shaibani A., Shchelochkov O.A., Zhang S., Katsonis P., Lichtarge O., RA Wong L.J., Shinawi M.; RT "Mitochondrial neurogastrointestinal encephalopathy due to mutations in RT RRM2B."; RL Arch. Neurol. 66:1028-1032(2009). RN [21] RP VARIANT SER-33. RX PubMed=26741492; DOI=10.1371/journal.pgen.1005679; RA Kohda M., Tokuzawa Y., Kishita Y., Nyuzuki H., Moriyama Y., Mizuno Y., RA Hirata T., Yatsuka Y., Yamashita-Sugahara Y., Nakachi Y., Kato H., RA Okuda A., Tamaru S., Borna N.N., Banshoya K., Aigaki T., Sato-Miyata Y., RA Ohnuma K., Suzuki T., Nagao A., Maehata H., Matsuda F., Higasa K., RA Nagasaki M., Yasuda J., Yamamoto M., Fushimi T., Shimura M., RA Kaiho-Ichimoto K., Harashima H., Yamazaki T., Mori M., Murayama K., RA Ohtake A., Okazaki Y.; RT "A comprehensive genomic analysis reveals the genetic landscape of RT mitochondrial respiratory chain complex deficiencies."; RL PLoS Genet. 12:E1005679-E1005679(2016). RN [22] RP VARIANT RCDFRD ASP-262, AND INVOLVEMENT IN RCDFRD. RX PubMed=32827185; DOI=10.1002/humu.24094; RA Roberts L., Julius S., Dawlat S., Yildiz S., Rebello G., Meldau S., RA Pillay K., Esterhuizen A., Vorster A., Benefeld G., da Rocha J., RA Beighton P., Sellars S.L., Thandrayen K., Pettifor J.M., Ramesar R.S.; RT "Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss RT caused by a mutation in RRM2B."; RL Hum. Mutat. 41:1871-1876(2020). CC -!- FUNCTION: Plays a pivotal role in cell survival by repairing damaged CC DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for CC DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free CC radical center required for catalysis. Forms an active ribonucleotide CC reductase (RNR) complex with RRM1 which is expressed both in resting CC and proliferating cells in response to DNA damage. CC {ECO:0000269|PubMed:10716435, ECO:0000269|PubMed:11517226, CC ECO:0000269|PubMed:11719458}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 2'-deoxyribonucleoside 5'-diphosphate + [thioredoxin]- CC disulfide + H2O = a ribonucleoside 5'-diphosphate + [thioredoxin]- CC dithiol; Xref=Rhea:RHEA:23252, Rhea:RHEA-COMP:10698, Rhea:RHEA- CC COMP:10700, ChEBI:CHEBI:15377, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:73316; EC=1.17.4.1; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10014, CC ECO:0000269|PubMed:16376858}; CC -!- COFACTOR: CC Name=Fe cation; Xref=ChEBI:CHEBI:24875; CC Evidence={ECO:0000269|PubMed:19728742}; CC Note=Binds 2 iron ions per subunit. {ECO:0000269|PubMed:19728742}; CC -!- SUBUNIT: Heterotetramer with large (RRM1) subunit. Interacts with CC p53/TP53. Interacts with RRM1 in response to DNA damage. CC {ECO:0000269|PubMed:11517226, ECO:0000269|PubMed:12615712, CC ECO:0000269|PubMed:16376858, ECO:0000269|PubMed:19728742, CC ECO:0000269|Ref.17}. CC -!- INTERACTION: CC Q7LG56; Q13315: ATM; NbExp=3; IntAct=EBI-9009083, EBI-495465; CC Q7LG56; Q00987: MDM2; NbExp=2; IntAct=EBI-9009083, EBI-389668; CC Q7LG56; O43929: ORC4; NbExp=4; IntAct=EBI-9009083, EBI-374889; CC Q7LG56; Q9H4P4: RNF41; NbExp=3; IntAct=EBI-9009083, EBI-2130266; CC Q7LG56; Q7LG56: RRM2B; NbExp=3; IntAct=EBI-9009083, EBI-9009083; CC Q7LG56-1; Q00987: MDM2; NbExp=2; IntAct=EBI-15741413, EBI-389668; CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Translocates from CC cytoplasm to nucleus in response to DNA damage. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=6; CC Name=1; CC IsoId=Q7LG56-1; Sequence=Displayed; CC Name=2; Synonyms=Long form; CC IsoId=Q7LG56-2; Sequence=VSP_017670; CC Name=3; Synonyms=Short form gamma; CC IsoId=Q7LG56-3; Sequence=VSP_017669; CC Name=4; Synonyms=Short form beta; CC IsoId=Q7LG56-4; Sequence=VSP_017668; CC Name=5; Synonyms=Short form; CC IsoId=Q7LG56-5; Sequence=VSP_017671, VSP_017672; CC Name=6; CC IsoId=Q7LG56-6; Sequence=VSP_053585; CC -!- TISSUE SPECIFICITY: Widely expressed at a high level in skeletal muscle CC and at a weak level in thymus. Expressed in epithelial dysplasias and CC squamous cell carcinoma. {ECO:0000269|PubMed:14583450}. CC -!- INDUCTION: In response to DNA damage in a wild-type p53/TP53-dependent CC manner. {ECO:0000269|PubMed:10716435}. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 8A (MTDPS8A) CC [MIM:612075]: A disorder due to mitochondrial dysfunction characterized CC by various combinations of neonatal hypotonia, neurological CC deterioration, respiratory distress, lactic acidosis, and renal CC tubulopathy. {ECO:0000269|PubMed:17486094, CC ECO:0000269|PubMed:18504129}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Mitochondrial DNA depletion syndrome 8B (MTDPS8B) CC [MIM:612075]: A disease due to mitochondrial dysfunction and CC characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, CC cachexia, peripheral neuropathy. {ECO:0000269|PubMed:19667227}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- DISEASE: Progressive external ophthalmoplegia with mitochondrial DNA CC deletions, autosomal dominant, 5 (PEOA5) [MIM:613077]: A disorder CC characterized by progressive weakness of ocular muscles and levator CC muscle of the upper eyelid. In a minority of cases, it is associated CC with skeletal myopathy, which predominantly involves axial or proximal CC muscles and which causes abnormal fatigability and even permanent CC muscle weakness. Ragged-red fibers and atrophy are found on muscle CC biopsy. A large proportion of chronic ophthalmoplegias are associated CC with other symptoms, leading to a multisystemic pattern of this CC disease. Additional symptoms are variable, and may include cataracts, CC hearing loss, sensory axonal neuropathy, ataxia, depression, CC hypogonadism, and parkinsonism. {ECO:0000269|PubMed:19664747}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Rod-cone dystrophy, sensorineural deafness, and Fanconi-type CC renal dysfunction (RCDFRD) [MIM:268315]: An autosomal recessive disease CC characterized by visual impairment due to rod-cone dystrophy, CC sensorineural hearing loss, and Fanconi-type renal dysfunction CC resulting in rickets-like skeletal changes. Death may occur in CC childhood or young adulthood due to renal failure. Disease onset is CC before age 5 years. {ECO:0000269|PubMed:32827185}. Note=The disease is CC caused by variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA CC decay. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the ribonucleoside diphosphate reductase small CC chain family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG65196.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=EAW91842.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AB036063; BAA92434.1; -; mRNA. DR EMBL; AB036532; BAA92493.1; -; Genomic_DNA. DR EMBL; AB163437; BAD11774.1; -; mRNA. DR EMBL; AB163438; BAD11775.1; -; mRNA. DR EMBL; AB166669; BAD12265.1; -; mRNA. DR EMBL; AB166670; BAD12266.1; -; mRNA. DR EMBL; AB166671; BAD12267.1; -; mRNA. DR EMBL; AK001965; BAA92005.1; -; mRNA. DR EMBL; AK304354; BAG65196.1; ALT_INIT; mRNA. DR EMBL; DC308409; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AL137348; CAB70703.2; -; mRNA. DR EMBL; DQ027001; AAY29059.1; -; Genomic_DNA. DR EMBL; AP001328; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP002907; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471060; EAW91842.1; ALT_SEQ; Genomic_DNA. DR EMBL; BC042468; AAH42468.1; -; mRNA. DR EMBL; BC108261; AAI08262.1; -; mRNA. DR EMBL; BC117496; AAI17497.1; -; mRNA. DR EMBL; BC130628; AAI30629.1; -; mRNA. DR CCDS; CCDS34932.1; -. [Q7LG56-1] DR CCDS; CCDS55267.1; -. [Q7LG56-2] DR PIR; T46249; T46249. DR RefSeq; NP_001165948.1; NM_001172477.1. [Q7LG56-6] DR RefSeq; NP_001165949.1; NM_001172478.2. [Q7LG56-2] DR RefSeq; NP_056528.2; NM_015713.4. [Q7LG56-1] DR PDB; 2VUX; X-ray; 2.80 A; A/B=20-322. DR PDB; 3HF1; X-ray; 2.60 A; A/B=1-351. DR PDB; 4DJN; X-ray; 2.20 A; A/B=13-322. DR PDBsum; 2VUX; -. DR PDBsum; 3HF1; -. DR PDBsum; 4DJN; -. DR AlphaFoldDB; Q7LG56; -. DR SMR; Q7LG56; -. DR BioGRID; 119071; 74. DR ComplexPortal; CPX-369; Ribonucleoside-diphosphate reductase RR1 complex, RRM2B variant. DR CORUM; Q7LG56; -. DR DIP; DIP-24264N; -. DR DIP; DIP-48627N; -. DR FunCoup; Q7LG56; 2091. DR IntAct; Q7LG56; 34. DR STRING; 9606.ENSP00000251810; -. DR BindingDB; Q7LG56; -. DR ChEMBL; CHEMBL3301398; -. DR DrugBank; DB00242; Cladribine. DR DrugBank; DB00631; Clofarabine. DR DrugBank; DB12948; Didox. DR GlyGen; Q7LG56; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q7LG56; -. DR PhosphoSitePlus; Q7LG56; -. DR BioMuta; RRM2B; -. DR DMDM; 74727333; -. DR jPOST; Q7LG56; -. DR MassIVE; Q7LG56; -. DR PaxDb; 9606-ENSP00000251810; -. DR PeptideAtlas; Q7LG56; -. DR ProteomicsDB; 5837; -. DR ProteomicsDB; 68860; -. [Q7LG56-1] DR ProteomicsDB; 68861; -. [Q7LG56-2] DR ProteomicsDB; 68862; -. [Q7LG56-3] DR ProteomicsDB; 68863; -. [Q7LG56-4] DR ProteomicsDB; 68864; -. [Q7LG56-5] DR Pumba; Q7LG56; -. DR Antibodypedia; 3483; 343 antibodies from 38 providers. DR DNASU; 50484; -. DR Ensembl; ENST00000251810.8; ENSP00000251810.3; ENSG00000048392.14. [Q7LG56-1] DR Ensembl; ENST00000395912.6; ENSP00000379248.2; ENSG00000048392.14. [Q7LG56-2] DR Ensembl; ENST00000519317.5; ENSP00000430641.1; ENSG00000048392.14. [Q7LG56-3] DR Ensembl; ENST00000519962.5; ENSP00000429140.1; ENSG00000048392.14. [Q7LG56-4] DR Ensembl; ENST00000522394.1; ENSP00000429578.1; ENSG00000048392.14. [Q7LG56-5] DR GeneID; 50484; -. DR KEGG; hsa:50484; -. DR MANE-Select; ENST00000251810.8; ENSP00000251810.3; NM_015713.5; NP_056528.2. DR UCSC; uc003ykn.4; human. [Q7LG56-1] DR AGR; HGNC:17296; -. DR ClinPGx; PA34866; -. DR CTD; 50484; -. DR DisGeNET; 50484; -. DR GeneCards; RRM2B; -. DR GeneReviews; RRM2B; -. DR HGNC; HGNC:17296; RRM2B. DR HPA; ENSG00000048392; Low tissue specificity. DR MalaCards; RRM2B; -. DR MIM; 268315; phenotype. DR MIM; 604712; gene. DR MIM; 612075; phenotype. DR MIM; 613077; phenotype. DR OpenTargets; ENSG00000048392; -. DR Orphanet; 329336; Adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy. DR Orphanet; 254892; Autosomal dominant progressive external ophthalmoplegia. DR Orphanet; 480; Kearns-Sayre syndrome. DR Orphanet; 255235; Mitochondrial DNA depletion syndrome, encephalomyopathic form with renal tubulopathy. DR Orphanet; 298; Mitochondrial neurogastrointestinal encephalomyopathy. DR VEuPathDB; HostDB:ENSG00000048392; -. DR eggNOG; KOG1567; Eukaryota. DR GeneTree; ENSGT00390000013305; -. DR HOGENOM; CLU_035339_2_0_1; -. DR InParanoid; Q7LG56; -. DR OMA; LEPMFLG; -. DR OrthoDB; 10248373at2759; -. DR PAN-GO; Q7LG56; 3 GO annotations based on evolutionary models. DR PhylomeDB; Q7LG56; -. DR BRENDA; 1.17.4.1; 2681. DR PathwayCommons; Q7LG56; -. DR Reactome; R-HSA-499943; Interconversion of nucleotide di- and triphosphates. DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes. DR SignaLink; Q7LG56; -. DR SIGNOR; Q7LG56; -. DR Agora; ENSG00000048392; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 50484; 17 hits in 1170 CRISPR screens. DR ChiTaRS; RRM2B; human. DR EvolutionaryTrace; Q7LG56; -. DR GeneWiki; RRM2B; -. DR GenomeRNAi; 50484; -. DR Pharos; Q7LG56; Tbio. DR PRO; PR:Q7LG56; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; Q7LG56; protein. DR Bgee; ENSG00000048392; Expressed in secondary oocyte and 188 other cell types or tissues. DR ExpressionAtlas; Q7LG56; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005739; C:mitochondrion; IEA:GOC. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005971; C:ribonucleoside-diphosphate reductase complex; ISS:ComplexPortal. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0004748; F:ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor; IBA:GO_Central. DR GO; GO:0009265; P:2'-deoxyribonucleotide biosynthetic process; IDA:ComplexPortal. DR GO; GO:0009200; P:deoxyribonucleoside triphosphate metabolic process; IEA:Ensembl. DR GO; GO:0009263; P:deoxyribonucleotide biosynthetic process; IBA:GO_Central. DR GO; GO:0006281; P:DNA repair; IDA:ComplexPortal. DR GO; GO:0000731; P:DNA synthesis involved in DNA repair; NAS:ComplexPortal. DR GO; GO:0001822; P:kidney development; IEA:Ensembl. DR GO; GO:0006264; P:mitochondrial DNA replication; IMP:ComplexPortal. DR GO; GO:1902254; P:negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator; IEA:Ensembl. DR GO; GO:0070318; P:positive regulation of G0 to G1 transition; IDA:ComplexPortal. DR GO; GO:0010971; P:positive regulation of G2/M transition of mitotic cell cycle; IDA:ComplexPortal. DR GO; GO:0003014; P:renal system process; IEA:Ensembl. DR GO; GO:0014075; P:response to amine; IEA:Ensembl. DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl. DR GO; GO:0009185; P:ribonucleoside diphosphate metabolic process; IDA:ComplexPortal. DR CDD; cd01049; RNRR2; 1. DR FunFam; 1.10.620.20:FF:000004; Ribonucleoside-diphosphate reductase subunit M2 B; 1. DR Gene3D; 1.10.620.20; Ribonucleotide Reductase, subunit A; 1. DR InterPro; IPR009078; Ferritin-like_SF. DR InterPro; IPR012348; RNR-like. DR InterPro; IPR033909; RNR_small. DR InterPro; IPR030475; RNR_small_AS. DR InterPro; IPR000358; RNR_small_fam. DR PANTHER; PTHR23409; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE SMALL CHAIN; 1. DR PANTHER; PTHR23409:SF19; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE SUBUNIT M2 B; 1. DR Pfam; PF00268; Ribonuc_red_sm; 1. DR SUPFAM; SSF47240; Ferritin-like; 1. DR PROSITE; PS00368; RIBORED_SMALL; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Deafness; KW Deoxyribonucleotide synthesis; Disease variant; DNA damage; DNA repair; KW Iron; Metal-binding; Neuropathy; Nucleus; Oxidoreductase; KW Primary mitochondrial disease; Progressive external ophthalmoplegia; KW Proteomics identification; Reference proteome. FT CHAIN 1..351 FT /note="Ribonucleoside-diphosphate reductase subunit M2 B" FT /id="PRO_0000228150" FT REGION 1..32 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT ACT_SITE 138 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10014" FT BINDING 100 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 131 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 131 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 134 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="1" FT BINDING 194 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 228 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT BINDING 231 FT /ligand="Fe cation" FT /ligand_id="ChEBI:CHEBI:24875" FT /ligand_label="2" FT VAR_SEQ 1..16 FT /note="MGDPERPEAAGLDQDE -> MLLLRLPPHRSHASPLDCKLQDRCRKCYSPRS FT GQACPPALAAAWLRRCERRGGRPRGGRRKELTLGLRPARCSAPGPAKDDAWRPQAG FT (in isoform 6)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053585" FT VAR_SEQ 17..301 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017668" FT VAR_SEQ 17..228 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017669" FT VAR_SEQ 17..68 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017670" FT VAR_SEQ 42..43 FT /note="FV -> SF (in isoform 5)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017671" FT VAR_SEQ 44..351 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|Ref.2" FT /id="VSP_017672" FT VARIANT 33 FT /note="P -> S (found in a patient with combined respiratory FT complex deficiencies, muscle weakness and hearing loss; FT uncertain significance; dbSNP:rs387906892)" FT /evidence="ECO:0000269|PubMed:26741492" FT /id="VAR_076280" FT VARIANT 64 FT /note="W -> R (in MTDPS8A; dbSNP:rs515726182)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046217" FT VARIANT 85 FT /note="Missing (in MTDPS8A; dbSNP:rs515726184)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046218" FT VARIANT 110 FT /note="R -> H (in MTDPS8B; dbSNP:rs267607025)" FT /evidence="ECO:0000269|PubMed:19667227" FT /id="VAR_065122" FT VARIANT 115 FT /note="V -> L (in colorectal adenocarcinomas cell line; FT loss of ribonucleotide reductase activity)" FT /evidence="ECO:0000269|PubMed:11719458" FT /id="VAR_025699" FT VARIANT 121 FT /note="R -> H (in MTDPS8B; dbSNP:rs267607024)" FT /evidence="ECO:0000269|PubMed:19667227" FT /id="VAR_065123" FT VARIANT 194 FT /note="E -> G (in MTDPS8A; dbSNP:rs515726191)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046219" FT VARIANT 194 FT /note="E -> K (in MTDPS8A; dbSNP:rs121918308)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046220" FT VARIANT 224 FT /note="I -> S (in MTDPS8A; without tubulopathy; FT dbSNP:rs515726196)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046221" FT VARIANT 236 FT /note="C -> F (in MTDPS8A; dbSNP:rs121918309)" FT /evidence="ECO:0000269|PubMed:17486094" FT /id="VAR_046222" FT VARIANT 262 FT /note="E -> D (in RCDFRD; dbSNP:rs1810682433)" FT /evidence="ECO:0000269|PubMed:32827185" FT /id="VAR_086956" FT VARIANT 282 FT /note="M -> I (in MTDPS8A; without tubulopathy; FT dbSNP:rs182614164)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046223" FT VARIANT 317 FT /note="L -> V (in MTDPS8A; without tubulopathy; FT dbSNP:rs515726198)" FT /evidence="ECO:0000269|PubMed:18504129" FT /id="VAR_046224" FT CONFLICT 277 FT /note="M -> V (in Ref. 3; BAA92005)" FT /evidence="ECO:0000305" FT HELIX 29..31 FT /evidence="ECO:0007829|PDB:4DJN" FT TURN 33..35 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 37..39 FT /evidence="ECO:0007829|PDB:4DJN" FT STRAND 42..44 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 50..61 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 66..68 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 74..78 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 83..109 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 111..114 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 118..145 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 149..156 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 158..161 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 163..177 FT /evidence="ECO:0007829|PDB:4DJN" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 183..195 FT /evidence="ECO:0007829|PDB:4DJN" FT TURN 196..198 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 199..210 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 215..240 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 248..267 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 272..275 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 279..296 FT /evidence="ECO:0007829|PDB:4DJN" FT HELIX 310..312 FT /evidence="ECO:0007829|PDB:4DJN" SQ SEQUENCE 351 AA; 40737 MW; 6D008687EEF40994 CRC64; MGDPERPEAA GLDQDERSSS DTNESEIKSN EEPLLRKSSR RFVIFPIQYP DIWKMYKQAQ ASFWTAEEVD LSKDLPHWNK LKADEKYFIS HILAFFAASD GIVNENLVER FSQEVQVPEA RCFYGFQILI ENVHSEMYSL LIDTYIRDPK KREFLFNAIE TMPYVKKKAD WALRWIADRK STFGERVVAF AAVEGVFFSG SFAAIFWLKK RGLMPGLTFS NELISRDEGL HCDFACLMFQ YLVNKPSEER VREIIVDAVK IEQEFLTEAL PVGLIGMNCI LMKQYIEFVA DRLLVELGFS KVFQAENPFD FMENISLEGK TNFFEKRVSE YQRFAVMAET TDNVFTLDAD F //