DPOLA_HUMAN
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 03-AUG-2022, entry version 211.
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/";
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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; 7OPL; EM; 4.12 A; A=334-1462.
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; 7OPL; -.
DR AlphaFoldDB; P09884; -.
DR SMR; P09884; -.
DR BioGRID; 111418; 91.
DR ComplexPortal; CPX-2087; DNA polymerase alpha:primase complex.
DR CORUM; P09884; -.
DR IntAct; P09884; 21.
DR MINT; P09884; -.
DR STRING; 9606.ENSP00000368349; -.
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 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; P09884; -.
DR PeptideAtlas; P09884; -.
DR PRIDE; P09884; -.
DR ProteomicsDB; 52272; -.
DR Antibodypedia; 498; 192 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 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 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; 334 hits in 721 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 157 other tissues.
DR ExpressionAtlas; P09884; baseline and differential.
DR Genevisible; P09884; HS.
DR GO; GO:0005658; C:alpha DNA polymerase:primase complex; 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:0017076; F:purine nucleotide binding; IBA:GO_Central.
DR GO; GO:0019103; F:pyrimidine nucleotide binding; IBA:GO_Central.
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; cd05532; POLBc_alpha; 1.
DR Gene3D; 1.10.132.60; -; 1.
DR Gene3D; 1.10.3200.20; -; 1.
DR Gene3D; 3.30.420.10; -; 1.
DR Gene3D; 3.90.1600.10; -; 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 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; SSF53098; SSF53098; 1.
DR SUPFAM; SSF56672; SSF56672; 1.
DR PROSITE; PS00116; DNA_POLYMERASE_B; 1.
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 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 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 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 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 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"
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
