ID DPOLA_HUMAN Reviewed; 1462 AA. AC P09884; Q86UQ7; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-2005, sequence version 2. DT 27-MAR-2024, entry version 220. DE RecName: Full=DNA polymerase alpha catalytic subunit; DE EC=2.7.7.7 {ECO:0000269|PubMed:893425, ECO:0000269|PubMed:9518481}; DE AltName: Full=DNA polymerase alpha catalytic subunit p180; GN Name=POLA1; Synonyms=POLA; 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=3359994; DOI=10.1002/j.1460-2075.1988.tb02781.x; RA Wong S.W., Wahl A.F., Yuan P.-M., Arai N., Pearson B.E., Arai K., Korn D., RA Hunkapiller M.W., Wang T.S.-F.; RT "Human DNA polymerase alpha gene expression is cell proliferation dependent RT and its primary structure is similar to both prokaryotic and eukaryotic RT replicative DNA polymerases."; RL EMBO J. 7:37-47(1988). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-8. RX PubMed=2005899; DOI=10.1128/mcb.11.4.2081-2095.1991; RA Pearson B.E., Nasheuer H.-P., Wang T.S.-F.; RT "Human DNA polymerase alpha gene: sequences controlling expression in RT cycling and serum-stimulated cells."; RL Mol. Cell. Biol. 11:2081-2095(1991). RN [4] RP PROTEIN SEQUENCE OF 19-37 AND 1405-1426, AND PROTEOLYTIC PROCESSING AT RP LYS-124. RX PubMed=2243771; DOI=10.1093/nar/18.21.6231; RA Hsi K.-L., Copeland W.C., Wang T.S.-F.; RT "Human DNA polymerase alpha catalytic polypeptide binds ConA and RCA and RT contains a specific labile site in the N-terminus."; RL Nucleic Acids Res. 18:6231-6237(1990). RN [5] RP CATALYTIC ACTIVITY. RX PubMed=893425; DOI=10.1016/s0021-9258(17)39990-8; RA Fisher P.A., Korn D.; RT "DNA polymerase-alpha. Purification and structural characterization of the RT near homogeneous enzyme from human KB cells."; RL J. Biol. Chem. 252:6528-6535(1977). RN [6] RP INTERACTION WITH SV40 LARGE T ANTIGEN (MICROBIAL INFECTION). RX PubMed=3025630; DOI=10.1128/mcb.6.11.4077-4087.1986; RA Smale S.T., Tjian R.; RT "T-antigen-DNA polymerase alpha complex implicated in simian virus 40 DNA RT replication."; RL Mol. Cell. Biol. 6:4077-4087(1986). RN [7] RP INTERACTION WITH HHV-1 UL9 PROTEIN (MICROBIAL INFECTION). RX PubMed=7644508; DOI=10.1073/pnas.92.17.7882; RA Lee S.S., Dong Q., Wang T.S., Lehman I.R.; RT "Interaction of herpes simplex virus 1 origin-binding protein with DNA RT polymerase alpha."; RL Proc. Natl. Acad. Sci. U.S.A. 92:7882-7886(1995). RN [8] RP INTERACTION WITH RPA1. RX PubMed=9214288; DOI=10.1021/bi970473r; RA Braun K.A., Lao Y., He Z., Ingles C.J., Wold M.S.; RT "Role of protein-protein interactions in the function of replication RT protein A (RPA): RPA modulates the activity of DNA polymerase alpha by RT multiple mechanisms."; RL Biochemistry 36:8443-8454(1997). RN [9] RP IDENTIFICATION IN THE DNA POLYMERASE ALPHA COMPLEX. RX PubMed=9705292; DOI=10.1074/jbc.273.34.21608; RA Schneider A., Smith R.W., Kautz A.R., Weisshart K., Grosse F., RA Nasheuer H.P.; RT "Primase activity of human DNA polymerase alpha-primase. Divalent cations RT stabilize the enzyme activity of the p48 subunit."; RL J. Biol. Chem. 273:21608-21615(1998). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH PARP1. RX PubMed=9518481; DOI=10.1093/nar/26.8.1891; RA Dantzer F., Nasheuer H.P., Vonesch J.L., de Murcia G., RA Menissier-de Murcia J.; RT "Functional association of poly(ADP-ribose) polymerase with DNA polymerase RT alpha-primase complex: a link between DNA strand break detection and DNA RT replication."; RL Nucleic Acids Res. 26:1891-1898(1998). RN [11] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186; SER-190 AND SER-209, AND RP IDENTIFICATION BY MASS 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 [12] RP INTERACTION WITH MCM10. RX PubMed=19608746; DOI=10.1074/jbc.m109.020438; RA Warren E.M., Huang H., Fanning E., Chazin W.J., Eichman B.F.; RT "Physical interactions between Mcm10, DNA, and DNA polymerase alpha."; RL J. Biol. Chem. 284:24662-24672(2009). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-174 AND SER-186, AND RP IDENTIFICATION BY 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 [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-174; SER-186; SER-190 AND RP SER-209, AND 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 [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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186 AND SER-209, 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 [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186; SER-190; SER-209 AND RP THR-406, AND IDENTIFICATION 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 [18] RP INVOLVEMENT IN PDR, FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=27019227; DOI=10.1038/ni.3409; RA Starokadomskyy P., Gemelli T., Rios J.J., Xing C., Wang R.C., Li H., RA Pokatayev V., Dozmorov I., Khan S., Miyata N., Fraile G., Raj P., Xu Z., RA Xu Z., Ma L., Lin Z., Wang H., Yang Y., Ben-Amitai D., Orenstein N., RA Mussaffi H., Baselga E., Tadini G., Grunebaum E., Sarajlija A., RA Krzewski K., Wakeland E.K., Yan N., de la Morena M.T., Zinn A.R., RA Burstein E.; RT "DNA polymerase-alpha regulates the activation of type I interferons RT through cytosolic RNA:DNA synthesis."; RL Nat. Immunol. 17:495-504(2016). RN [19] RP STRUCTURE BY NMR OF 1345-1382. RX PubMed=14499601; DOI=10.1016/s1570-9639(03)00266-8; RA Evanics F., Maurmann L., Yang W.W., Bose R.N.; RT "Nuclear magnetic resonance structures of the zinc finger domain of human RT DNA polymerase-alpha."; RL Biochim. Biophys. Acta 1651:163-171(2003). RN [20] {ECO:0007744|PDB:5EXR} RP X-RAY CRYSTALLOGRAPHY (3.60 ANGSTROMS) OF 335-1462 IN COMPLEX WITH ZINC, RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND SUBUNIT. RX PubMed=26975377; DOI=10.1074/jbc.m116.717405; RA Baranovskiy A.G., Babayeva N.D., Zhang Y., Gu J., Suwa Y., Pavlov Y.I., RA Tahirov T.H.; RT "Mechanism of Concerted RNA-DNA Primer Synthesis by the Human Primosome."; RL J. Biol. Chem. 291:10006-10020(2016). RN [21] RP INVOLVEMENT IN VEODS, VARIANTS VEODS SER-79; ARG-110 AND LEU-1381, RP CHARACTERIZATION OF VARIANTS VEODS SER-79 AND LEU-1381, AND FUNCTION. RX PubMed=31006512; DOI=10.1016/j.ajhg.2019.03.006; RA Van Esch H., Colnaghi R., Freson K., Starokadomskyy P., Zankl A., Backx L., RA Abramowicz I., Outwin E., Rohena L., Faulkner C., Leong G.M., RA Newbury-Ecob R.A., Challis R.C., Ounap K., Jaeken J., Seuntjens E., RA Devriendt K., Burstein E., Low K.J., O'Driscoll M.; RT "Defective DNA Polymerase alpha-Primase Leads to X-Linked Intellectual RT Disability Associated with Severe Growth Retardation, Microcephaly, and RT Hypogonadism."; RL Am. J. Hum. Genet. 104:957-967(2019). CC -!- FUNCTION: Catalytic subunit of the DNA polymerase alpha complex (also CC known as the alpha DNA polymerase-primase complex) which plays an CC essential role in the initiation of DNA synthesis. During the S phase CC of the cell cycle, the DNA polymerase alpha complex (composed of a CC catalytic subunit POLA1, a regulatory subunit POLA2 and two primase CC subunits PRIM1 and PRIM2) is recruited to DNA at the replicative forks CC via direct interactions with MCM10 and WDHD1. The primase subunit of CC the polymerase alpha complex initiates DNA synthesis by oligomerising CC short RNA primers on both leading and lagging strands. These primers CC are initially extended by the polymerase alpha catalytic subunit and CC subsequently transferred to polymerase delta and polymerase epsilon for CC processive synthesis on the lagging and leading strand, respectively. CC The reason this transfer occurs is because the polymerase alpha has CC limited processivity and lacks intrinsic 3' exonuclease activity for CC proofreading error, and therefore is not well suited for replicating CC long complexes. In the cytosol, responsible for a substantial CC proportion of the physiological concentration of cytosolic RNA:DNA CC hybrids, which are necessary to prevent spontaneous activation of type CC I interferon responses (PubMed:27019227). {ECO:0000269|PubMed:26975377, CC ECO:0000269|PubMed:27019227, ECO:0000269|PubMed:31006512, CC ECO:0000269|PubMed:9518481}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 2'-deoxyribonucleoside 5'-triphosphate + DNA(n) = CC diphosphate + DNA(n+1); Xref=Rhea:RHEA:22508, Rhea:RHEA-COMP:17339, CC Rhea:RHEA-COMP:17340, ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, CC ChEBI:CHEBI:173112; EC=2.7.7.7; CC Evidence={ECO:0000269|PubMed:26975377, ECO:0000269|PubMed:893425, CC ECO:0000269|PubMed:9518481}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22509; CC Evidence={ECO:0000269|PubMed:26975377, ECO:0000269|PubMed:9518481}; CC -!- ACTIVITY REGULATION: Autoinhibited in apo-primosome, where the zinc CC motif of POLA1 and oligonucleotide/olicosaccharide-binding domain of CC POLA2 are placed into the active site blocking RNA:DNA duplex entry. CC {ECO:0000269|PubMed:26975377}. CC -!- SUBUNIT: Component of the alpha DNA polymerase complex (also known as CC the alpha DNA polymerase-primase complex) consisting of four subunits: CC the catalytic subunit POLA1, the regulatory subunit POLA2, and the CC primase complex subunits PRIM1 and PRIM2 respectively (PubMed:9705292, CC PubMed:26975377). Interacts with PARP1; this interaction functions as CC part of the control of replication fork progression (PubMed:9518481). CC Interacts with MCM10 and WDHD1; these interactions recruit the CC polymerase alpha complex to the pre-replicative complex bound to DNA CC (PubMed:19608746). Interacts with RPA1; this interaction stabilizes the CC replicative complex and reduces the misincorporation rate of DNA CC polymerase alpha by acting as a fidelity clamp (PubMed:9214288). CC {ECO:0000269|PubMed:19608746, ECO:0000269|PubMed:9214288, CC ECO:0000269|PubMed:9518481, ECO:0000269|PubMed:9705292}. CC -!- SUBUNIT: (Microbial infection) Interacts with SV40 Large T antigen; CC this interaction allows viral DNA replication. CC {ECO:0000269|PubMed:3025630}. CC -!- SUBUNIT: (Microbial infection) Interacts with herpes simplex virus CC 1/HHV-1 replication origin-binding protein UL9. CC {ECO:0000269|PubMed:7644508}. CC -!- INTERACTION: CC P09884; P27694: RPA1; NbExp=2; IntAct=EBI-850026, EBI-621389; CC P09884; P10193: UL9; Xeno; NbExp=4; IntAct=EBI-850026, EBI-8596799; CC P09884; P03070; Xeno; NbExp=6; IntAct=EBI-850026, EBI-617698; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:27019227}. Cytoplasm, CC cytosol {ECO:0000269|PubMed:27019227}. Note=In the cytosol, colocalizes CC with RNA:DNA hybrids with a speckled pattern. CC {ECO:0000269|PubMed:27019227}. CC -!- DOMAIN: The CysA-type zinc finger is required for PCNA-binding. CC {ECO:0000250|UniProtKB:P15436}. CC -!- PTM: A 165 kDa form is probably produced by proteolytic cleavage at CC Lys-124. {ECO:0000269|PubMed:2243771}. CC -!- DISEASE: Pigmentary disorder, reticulate, with systemic manifestations, CC X-linked (PDR) [MIM:301220]: An X-linked recessive disorder CC characterized by recurrent infections and sterile inflammation in CC various organs. Diffuse skin hyperpigmentation with a distinctive CC reticulate pattern is universally evident by early childhood. This is CC later followed in many patients by hypohidrosis, corneal inflammation CC and scarring, enterocolitis that resembles inflammatory bowel disease, CC and recurrent urethral strictures. Melanin and amyloid deposition is CC present in the dermis. Affected males also have a characteristic facies CC with frontally upswept hair and flared eyebrows. Female carriers have CC only restricted pigmentary changes along Blaschko's lines. CC {ECO:0000269|PubMed:27019227}. Note=The disease is caused by variants CC affecting the gene represented in this entry. XLPDR is caused by a CC recurrent intronic mutation that results in missplicing and reduced CC POLA1 expression. This leads to a decrease in cytosolic RNA:DNA hybrids CC and constitutive activation of type I interferon responses, but has no CC effect on cell replication. {ECO:0000269|PubMed:27019227}. CC -!- DISEASE: Van Esch-O'Driscoll syndrome (VEODS) [MIM:301030]: An X-linked CC recessive syndrome characterized by different degrees of intellectual CC disability, moderate to severe short stature, microcephaly, CC hypogonadism, and variable congenital malformations. CC {ECO:0000269|PubMed:31006512}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: In eukaryotes there are five DNA polymerases: alpha, CC beta, gamma, delta, and epsilon which are responsible for different CC reactions of DNA synthesis. CC -!- SIMILARITY: Belongs to the DNA polymerase type-B family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/pola/"; 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; X06745; CAA29920.1; -; mRNA. DR EMBL; AY275833; AAP13534.1; -; Genomic_DNA. DR EMBL; M64481; AAA52318.1; -; Genomic_DNA. DR CCDS; CCDS14214.1; -. DR PIR; S00257; DJHUAC. DR RefSeq; NP_058633.2; NM_016937.3. DR PDB; 1K0P; NMR; -; A=1347-1377. DR PDB; 1K18; NMR; -; A=1347-1377. DR PDB; 1N5G; NMR; -; A=1345-1382. DR PDB; 4Q5V; X-ray; 2.52 A; A/E=336-1257. DR PDB; 4QCL; X-ray; 2.20 A; A=336-1257. DR PDB; 4Y97; X-ray; 2.51 A; B/D/F/H=1265-1444. DR PDB; 5EXR; X-ray; 3.60 A; C/G=335-1462. DR PDB; 5IUD; X-ray; 3.30 A; A/D/G/J=338-1255. DR PDB; 6AS7; X-ray; 2.95 A; A=336-1257. DR PDB; 7N2M; X-ray; 2.90 A; A=336-1257. DR PDB; 7OPL; EM; 4.12 A; A=334-1462. DR PDB; 7U5C; EM; 4.60 A; C=335-1462. DR PDB; 8B9D; EM; 3.40 A; B=1-1462. DR PDB; 8D0B; EM; 3.43 A; F=324-1462. DR PDB; 8D0K; EM; 4.27 A; F=2-1462. DR PDB; 8D96; EM; 3.35 A; C=1-1462. DR PDB; 8D9D; EM; 3.59 A; C=1-1462. DR PDBsum; 1K0P; -. DR PDBsum; 1K18; -. DR PDBsum; 1N5G; -. DR PDBsum; 4Q5V; -. DR PDBsum; 4QCL; -. DR PDBsum; 4Y97; -. DR PDBsum; 5EXR; -. DR PDBsum; 5IUD; -. DR PDBsum; 6AS7; -. DR PDBsum; 7N2M; -. DR PDBsum; 7OPL; -. DR PDBsum; 7U5C; -. DR PDBsum; 8B9D; -. DR PDBsum; 8D0B; -. DR PDBsum; 8D0K; -. DR PDBsum; 8D96; -. DR PDBsum; 8D9D; -. DR AlphaFoldDB; P09884; -. DR EMDB; EMD-13020; -. DR EMDB; EMD-26346; -. DR EMDB; EMD-26347; -. DR EMDB; EMD-27104; -. DR EMDB; EMD-27107; -. DR EMDB; EMD-27256; -. DR EMDB; EMD-27258; -. DR EMDB; EMD-42033; -. DR EMDB; EMD-42034; -. DR EMDB; EMD-42035; -. DR EMDB; EMD-42036; -. DR EMDB; EMD-42037; -. DR SASBDB; P09884; -. DR SMR; P09884; -. DR BioGRID; 111418; 123. DR ComplexPortal; CPX-2087; DNA polymerase alpha:primase complex. DR CORUM; P09884; -. DR IntAct; P09884; 23. DR MINT; P09884; -. DR STRING; 9606.ENSP00000368358; -. DR BindingDB; P09884; -. DR ChEMBL; CHEMBL1828; -. DR DrugBank; DB00242; Cladribine. DR DrugBank; DB00631; Clofarabine. DR DrugBank; DB01073; Fludarabine. DR DrugBank; DB01280; Nelarabine. DR DrugCentral; P09884; -. DR CarbonylDB; P09884; -. DR GlyGen; P09884; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P09884; -. DR PhosphoSitePlus; P09884; -. DR BioMuta; POLA1; -. DR DMDM; 60392197; -. DR EPD; P09884; -. DR jPOST; P09884; -. DR MassIVE; P09884; -. DR MaxQB; P09884; -. DR PaxDb; 9606-ENSP00000368349; -. DR PeptideAtlas; P09884; -. DR ProteomicsDB; 52272; -. DR Pumba; P09884; -. DR Antibodypedia; 498; 217 antibodies from 28 providers. DR DNASU; 5422; -. DR Ensembl; ENST00000379059.7; ENSP00000368349.3; ENSG00000101868.13. DR GeneID; 5422; -. DR KEGG; hsa:5422; -. DR UCSC; uc004dbl.4; human. DR AGR; HGNC:9173; -. DR CTD; 5422; -. DR DisGeNET; 5422; -. DR GeneCards; POLA1; -. DR HGNC; HGNC:9173; POLA1. DR HPA; ENSG00000101868; Low tissue specificity. DR MalaCards; POLA1; -. DR MIM; 301030; phenotype. DR MIM; 301220; phenotype. DR MIM; 312040; gene. DR neXtProt; NX_P09884; -. DR OpenTargets; ENSG00000101868; -. DR Orphanet; 163976; X-linked intellectual disability, Van Esch type. DR Orphanet; 85453; X-linked reticulate pigmentary disorder. DR PharmGKB; PA162399856; -. DR VEuPathDB; HostDB:ENSG00000101868; -. DR eggNOG; KOG0970; Eukaryota. DR GeneTree; ENSGT00550000074891; -. DR HOGENOM; CLU_001718_0_0_1; -. DR InParanoid; P09884; -. DR OrthoDB; 5477697at2759; -. DR PhylomeDB; P09884; -. DR TreeFam; TF103001; -. DR BRENDA; 2.7.7.102; 2681. DR PathwayCommons; P09884; -. DR Reactome; R-HSA-113501; Inhibition of replication initiation of damaged DNA by RB1/E2F1. DR Reactome; R-HSA-174411; Polymerase switching on the C-strand of the telomere. DR Reactome; R-HSA-174430; Telomere C-strand synthesis initiation. DR Reactome; R-HSA-68952; DNA replication initiation. DR Reactome; R-HSA-68962; Activation of the pre-replicative complex. DR Reactome; R-HSA-69091; Polymerase switching. DR Reactome; R-HSA-69166; Removal of the Flap Intermediate. DR Reactome; R-HSA-69183; Processive synthesis on the lagging strand. DR Reactome; R-HSA-69205; G1/S-Specific Transcription. DR Reactome; R-HSA-9710421; Defective pyroptosis. DR SignaLink; P09884; -. DR SIGNOR; P09884; -. DR BioGRID-ORCS; 5422; 352 hits in 806 CRISPR screens. DR ChiTaRS; POLA1; human. DR EvolutionaryTrace; P09884; -. DR GeneWiki; Polymerase_(DNA_directed),_alpha_1; -. DR GenomeRNAi; 5422; -. DR Pharos; P09884; Tclin. DR PRO; PR:P09884; -. DR Proteomes; UP000005640; Chromosome X. DR RNAct; P09884; Protein. DR Bgee; ENSG00000101868; Expressed in ventricular zone and 158 other cell types or tissues. DR ExpressionAtlas; P09884; baseline and differential. DR GO; GO:0005658; C:alpha DNA polymerase:primase complex; IDA:UniProtKB. DR GO; GO:0000785; C:chromatin; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0005635; C:nuclear envelope; IDA:UniProtKB. DR GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB. DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0003688; F:DNA replication origin binding; IBA:GO_Central. DR GO; GO:0003887; F:DNA-directed DNA polymerase activity; IDA:UniProtKB. DR GO; GO:0000166; F:nucleotide binding; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:UniProtKB. DR GO; GO:0003697; F:single-stranded DNA binding; IBA:GO_Central. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; IMP:UniProtKB. DR GO; GO:0006260; P:DNA replication; IMP:UniProtKB. DR GO; GO:0006270; P:DNA replication initiation; IDA:UniProtKB. DR GO; GO:0006269; P:DNA replication, synthesis of RNA primer; IDA:UniProtKB. DR GO; GO:0006271; P:DNA strand elongation involved in DNA replication; IMP:UniProtKB. DR GO; GO:0000731; P:DNA synthesis involved in DNA repair; IMP:UniProtKB. DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IMP:UniProtKB. DR GO; GO:0006273; P:lagging strand elongation; IDA:UniProtKB. DR GO; GO:0006272; P:leading strand elongation; IDA:UniProtKB. DR GO; GO:1902975; P:mitotic DNA replication initiation; IBA:GO_Central. DR GO; GO:0032479; P:regulation of type I interferon production; IMP:UniProtKB. DR CDD; cd05776; DNA_polB_alpha_exo; 1. DR CDD; cd05532; POLBc_alpha; 1. DR Gene3D; 2.40.50.730; -; 1. DR Gene3D; 3.30.70.2820; -; 1. DR Gene3D; 1.10.3200.20; DNA Polymerase alpha, zinc finger; 1. DR Gene3D; 1.10.132.60; DNA polymerase family B, C-terminal domain; 1. DR Gene3D; 1.10.287.690; Helix hairpin bin; 1. DR Gene3D; 3.90.1600.10; Palm domain of DNA polymerase; 1. DR Gene3D; 3.30.420.10; Ribonuclease H-like superfamily/Ribonuclease H; 1. DR InterPro; IPR006172; DNA-dir_DNA_pol_B. DR InterPro; IPR017964; DNA-dir_DNA_pol_B_CS. DR InterPro; IPR006133; DNA-dir_DNA_pol_B_exonuc. DR InterPro; IPR006134; DNA-dir_DNA_pol_B_multi_dom. DR InterPro; IPR043502; DNA/RNA_pol_sf. DR InterPro; IPR024647; DNA_pol_a_cat_su_N. DR InterPro; IPR042087; DNA_pol_B_thumb. DR InterPro; IPR023211; DNA_pol_palm_dom_sf. DR InterPro; IPR038256; Pol_alpha_znc_sf. DR InterPro; IPR045846; POLBc_alpha. DR InterPro; IPR012337; RNaseH-like_sf. DR InterPro; IPR036397; RNaseH_sf. DR InterPro; IPR015088; Znf_DNA-dir_DNA_pol_B_alpha. DR NCBIfam; TIGR00592; pol2; 1. DR PANTHER; PTHR45861; DNA POLYMERASE ALPHA CATALYTIC SUBUNIT; 1. DR PANTHER; PTHR45861:SF1; DNA POLYMERASE ALPHA CATALYTIC SUBUNIT; 1. DR Pfam; PF12254; DNA_pol_alpha_N; 1. DR Pfam; PF00136; DNA_pol_B; 1. DR Pfam; PF03104; DNA_pol_B_exo1; 1. DR Pfam; PF08996; zf-DNA_Pol; 1. DR PRINTS; PR00106; DNAPOLB. DR SMART; SM00486; POLBc; 1. DR SUPFAM; SSF56672; DNA/RNA polymerases; 1. DR SUPFAM; SSF53098; Ribonuclease H-like; 1. DR SUPFAM; SSF90234; Zinc finger domain of DNA polymerase-alpha; 1. DR PROSITE; PS00116; DNA_POLYMERASE_B; 1. DR Genevisible; P09884; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cytoplasm; Direct protein sequencing; KW Disease variant; DNA replication; DNA-binding; DNA-directed DNA polymerase; KW Dwarfism; Host-virus interaction; Intellectual disability; Metal-binding; KW Nucleotidyltransferase; Nucleus; Phosphoprotein; Reference proteome; KW Transferase; Zinc; Zinc-finger. FT CHAIN 1..1462 FT /note="DNA polymerase alpha catalytic subunit" FT /id="PRO_0000046428" FT ZN_FING 1283..1318 FT /note="CysA-type" FT /evidence="ECO:0000250|UniProtKB:P15436" FT REGION 1..33 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 98..123 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 232..251 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 650..715 FT /note="DNA-binding" FT /evidence="ECO:0000255" FT REGION 1245..1376 FT /note="DNA-binding" FT /evidence="ECO:0000255" FT MOTIF 1348..1374 FT /note="CysB motif" FT /evidence="ECO:0000250|UniProtKB:P15436" FT COMPBIAS 106..123 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 233..251 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 1283 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1286 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1310 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1315 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1348 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1353 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1371 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT BINDING 1374 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:26975377, FT ECO:0007744|PDB:5EXR" FT SITE 124..125 FT /note="Cleavage" FT MOD_RES 174 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:20068231" FT MOD_RES 186 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT MOD_RES 190 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 209 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 224 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P33609" FT MOD_RES 406 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 970 FT /note="N6-succinyllysine" FT /evidence="ECO:0000250|UniProtKB:P33609" FT VARIANT 79 FT /note="I -> S (in VEODS; no effect on protein abundance; FT decreased DNA replication; dbSNP:rs1569271378)" FT /evidence="ECO:0000269|PubMed:31006512" FT /id="VAR_083194" FT VARIANT 110 FT /note="G -> R (in VEODS; decreased protein abundance; may FT alter splicing; dbSNP:rs1569271892)" FT /evidence="ECO:0000269|PubMed:31006512" FT /id="VAR_083195" FT VARIANT 740 FT /note="Y -> H (in dbSNP:rs2230927)" FT /id="VAR_048877" FT VARIANT 1381 FT /note="P -> L (in VEODS; no effect on protein abundance; FT decreased DNA replication; dbSNP:rs1569350993)" FT /evidence="ECO:0000269|PubMed:31006512" FT /id="VAR_083196" FT CONFLICT 503..506 FT /note="SPQL -> KSTA (in Ref. 1; CAA29920)" FT /evidence="ECO:0000305" FT CONFLICT 837 FT /note="A -> G (in Ref. 1; CAA29920)" FT /evidence="ECO:0000305" FT CONFLICT 1405 FT /note="L -> C (in Ref. 4; AA sequence)" FT /evidence="ECO:0000305" FT CONFLICT 1426 FT /note="V -> C (in Ref. 4; AA sequence)" FT /evidence="ECO:0000305" FT STRAND 326..328 FT /evidence="ECO:0007829|PDB:8D0B" FT STRAND 340..350 FT /evidence="ECO:0007829|PDB:4QCL" FT TURN 352..354 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 359..367 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 368..370 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 372..380 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 385..391 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 393..396 FT /evidence="ECO:0007829|PDB:4QCL" FT TURN 398..400 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 403..407 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 410..419 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 421..425 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 431..438 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 441..445 FT /evidence="ECO:0007829|PDB:5IUD" FT STRAND 448..457 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 471..477 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 483..491 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 495..503 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 512..522 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 523..525 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 526..529 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 537..548 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 550..552 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 555..568 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 570..572 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 576..578 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 580..586 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 590..592 FT /evidence="ECO:0007829|PDB:8D96" FT HELIX 598..605 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 609..611 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 615..629 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 632..638 FT /evidence="ECO:0007829|PDB:4QCL" FT TURN 639..642 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 643..653 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 659..662 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 663..665 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 679..684 FT /evidence="ECO:0007829|PDB:4QCL" FT TURN 685..687 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 688..692 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 693..700 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 708..716 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 725..732 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 735..758 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 761..772 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 776..779 FT /evidence="ECO:0007829|PDB:4QCL" FT TURN 780..782 FT /evidence="ECO:0007829|PDB:8D0B" FT HELIX 785..798 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 850..852 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 856..861 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 864..871 FT /evidence="ECO:0007829|PDB:4QCL" FT TURN 876..878 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 885..889 FT /evidence="ECO:0007829|PDB:8D0B" FT STRAND 891..894 FT /evidence="ECO:0007829|PDB:8D0B" FT HELIX 910..930 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 931..933 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 936..960 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 970..993 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 997..1000 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1002..1009 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1015..1030 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1038..1051 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1054..1062 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1068..1076 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1078..1080 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1082..1084 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1086..1099 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1101..1103 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1105..1125 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1130..1133 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1135..1138 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1143..1145 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1149..1151 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1153..1164 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1165..1167 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1174..1181 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1188..1190 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1195..1200 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1208..1214 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1216..1224 FT /evidence="ECO:0007829|PDB:4QCL" FT STRAND 1225..1227 FT /evidence="ECO:0007829|PDB:5IUD" FT HELIX 1232..1238 FT /evidence="ECO:0007829|PDB:4QCL" FT HELIX 1243..1245 FT /evidence="ECO:0007829|PDB:6AS7" FT HELIX 1269..1272 FT /evidence="ECO:0007829|PDB:4Y97" FT TURN 1273..1275 FT /evidence="ECO:0007829|PDB:4Y97" FT STRAND 1279..1282 FT /evidence="ECO:0007829|PDB:4Y97" FT TURN 1284..1286 FT /evidence="ECO:0007829|PDB:4Y97" FT STRAND 1289..1298 FT /evidence="ECO:0007829|PDB:4Y97" FT TURN 1306..1308 FT /evidence="ECO:0007829|PDB:8D0B" FT HELIX 1319..1322 FT /evidence="ECO:0007829|PDB:4Y97" FT HELIX 1323..1342 FT /evidence="ECO:0007829|PDB:4Y97" FT STRAND 1346..1349 FT /evidence="ECO:0007829|PDB:4Y97" FT TURN 1351..1353 FT /evidence="ECO:0007829|PDB:4Y97" FT STRAND 1356..1358 FT /evidence="ECO:0007829|PDB:4Y97" FT STRAND 1359..1362 FT /evidence="ECO:0007829|PDB:1K18" FT STRAND 1364..1367 FT /evidence="ECO:0007829|PDB:1N5G" FT STRAND 1368..1370 FT /evidence="ECO:0007829|PDB:4Y97" FT STRAND 1372..1383 FT /evidence="ECO:0007829|PDB:4Y97" FT HELIX 1385..1397 FT /evidence="ECO:0007829|PDB:4Y97" FT HELIX 1401..1406 FT /evidence="ECO:0007829|PDB:4Y97" FT HELIX 1411..1420 FT /evidence="ECO:0007829|PDB:4Y97" FT HELIX 1424..1434 FT /evidence="ECO:0007829|PDB:4Y97" FT HELIX 1445..1447 FT /evidence="ECO:0007829|PDB:8D0B" FT HELIX 1451..1454 FT /evidence="ECO:0007829|PDB:8D0B" FT TURN 1455..1457 FT /evidence="ECO:0007829|PDB:8D0B" SQ SEQUENCE 1462 AA; 165913 MW; DC40C3EDD6F4B495 CRC64; MAPVHGDDSL SDSGSFVSSR ARREKKSKKG RQEALERLKK AKAGEKYKYE VEDFTGVYEE VDEEQYSKLV QARQDDDWIV DDDGIGYVED GREIFDDDLE DDALDADEKG KDGKARNKDK RNVKKLAVTK PNNIKSMFIA CAGKKTADKA VDLSKDGLLG DILQDLNTET PQITPPPVMI LKKKRSIGAS PNPFSVHTAT AVPSGKIASP VSRKEPPLTP VPLKRAEFAG DDVQVESTEE EQESGAMEFE DGDFDEPMEV EEVDLEPMAA KAWDKESEPA EEVKQEADSG KGTVSYLGSF LPDVSCWDID QEGDSSFSVQ EVQVDSSHLP LVKGADEEQV FHFYWLDAYE DQYNQPGVVF LFGKVWIESA ETHVSCCVMV KNIERTLYFL PREMKIDLNT GKETGTPISM KDVYEEFDEK IATKYKIMKF KSKPVEKNYA FEIPDVPEKS EYLEVKYSAE MPQLPQDLKG ETFSHVFGTN TSSLELFLMN RKIKGPCWLE VKSPQLLNQP VSWCKVEAMA LKPDLVNVIK DVSPPPLVVM AFSMKTMQNA KNHQNEIIAM AALVHHSFAL DKAAPKPPFQ SHFCVVSKPK DCIFPYAFKE VIEKKNVKVE VAATERTLLG FFLAKVHKID PDIIVGHNIY GFELEVLLQR INVCKAPHWS KIGRLKRSNM PKLGGRSGFG ERNATCGRMI CDVEISAKEL IRCKSYHLSE LVQQILKTER VVIPMENIQN MYSESSQLLY LLEHTWKDAK FILQIMCELN VLPLALQITN IAGNIMSRTL MGGRSERNEF LLLHAFYENN YIVPDKQIFR KPQQKLGDED EEIDGDTNKY KKGRKKAAYA GGLVLDPKVG FYDKFILLLD FNSLYPSIIQ EFNICFTTVQ RVASEAQKVT EDGEQEQIPE LPDPSLEMGI LPREIRKLVE RRKQVKQLMK QQDLNPDLIL QYDIRQKALK LTANSMYGCL GFSYSRFYAK PLAALVTYKG REILMHTKEM VQKMNLEVIY GDTDSIMINT NSTNLEEVFK LGNKVKSEVN KLYKLLEIDI DGVFKSLLLL KKKKYAALVV EPTSDGNYVT KQELKGLDIV RRDWCDLAKD TGNFVIGQIL SDQSRDTIVE NIQKRLIEIG ENVLNGSVPV SQFEINKALT KDPQDYPDKK SLPHVHVALW INSQGGRKVK AGDTVSYVIC QDGSNLTASQ RAYAPEQLQK QDNLTIDTQY YLAQQIHPVV ARICEPIDGI DAVLIATWLG LDPTQFRVHH YHKDEENDAL LGGPAQLTDE EKYRDCERFK CPCPTCGTEN IYDNVFDGSG TDMEPSLYRC SNIDCKASPL TFTVQLSNKL IMDIRRFIKK YYDGWLICEE PTCRNRTRHL PLQFSRTGPL CPACMKATLQ PEYSDKSLYT QLCFYRYIFD AECALEKLTT DHEKDKLKKQ FFTPKVLQDY RKLKNTAEQF LSRSGYSEVN LSKLFAGCAV KS //