P09884 (DPOLA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
DNA polymerase alpha catalytic subunit
EC=2.7.7.7

Alternative name(s):
DNA polymerase alpha catalytic subunit p180

Gene names

Name:	POLA1
Synonyms:	POLA

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1462 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes. Ref.8
Catalytic activity	Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1).
Subunit structure	The DNA polymerase alpha complex is composed of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the small and the large primase subunits PRIM1 and PRIM2 respectively. Interacts with PARP1; this interaction functions as part of the control of replication fork progression. Interacts with MCM10 and WDHD1; these interactions recruit the polymerase alpha complex to the pre-replicative complex bound to DNA. Interacts with RPA1; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp. Interacts with SV40 Large T antigen; this interaction allows viral DNA replication. Interacts with herpes simplex virus 1 (HHV-1) replication origin-binding protein UL9. Ref.5 Ref.6 Ref.7 Ref.8 Ref.12
Subcellular location	Nucleus.
Post-translational modification	A 165 kDa form is probably produced by proteolytic cleavage at Lys-124.
Miscellaneous	In eukaryotes there are five DNA polymerases: alpha, beta, gamma, delta, and epsilon which are responsible for different reactions of DNA synthesis.
Sequence similarities	Belongs to the DNA polymerase type-B family.

Ontologies

Keywords
Biological process	DNA replication Host-virus interaction
Cellular component	Nucleus
Coding sequence diversity	Polymorphism
Domain	Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	DNA-directed DNA polymerase Nucleotidyltransferase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	DNA replication checkpoint Inferred from Biological aspect of Ancestor. Source: RefGenome DNA replication, synthesis of RNA primer Inferred from Biological aspect of Ancestor. Source: RefGenome DNA-dependent DNA replication initiation Inferred from direct assay. Source: UniProtKB M/G1 transition of mitotic cell cycle Traceable author statement. Source: Reactome S phase of mitotic cell cycle Inferred from direct assay. Source: UniProtKB cell proliferation Inferred from direct assay Ref.1. Source: UniProtKB double-strand break repair via nonhomologous end joining Inferred from mutant phenotype. Source: UniProtKB interspecies interaction between organisms Inferred from electronic annotation. Source: UniProtKB-KW lagging strand elongation Inferred from direct assay. Source: UniProtKB leading strand elongation Inferred from direct assay. Source: UniProtKB regulation of transcription involved in G1/S phase of mitotic cell cycle Traceable author statement. Source: Reactome telomere maintenance via recombination Traceable author statement. Source: Reactome telomere maintenance via semi-conservative replication Traceable author statement. Source: Reactome
Cellular component	alpha DNA polymerase:primase complex Inferred from direct assay. Source: UniProtKB cytoplasm Inferred from direct assay. Source: HPA nuclear envelope Inferred from direct assay Ref.8. Source: UniProtKB nuclear matrix Inferred from direct assay. Source: UniProtKB nucleolus Inferred from direct assay Ref.8. Source: UniProtKB nucleoplasm Inferred from direct assay. Source: UniProtKB
Molecular function	DNA-directed DNA polymerase activity Inferred from direct assay Ref.1. Source: UniProtKB chromatin binding Inferred from direct assay. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW nucleoside binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 1462

1462

DNA polymerase alpha catalytic subunit

PRO_0000046428

Regions

DNA binding

650 – 715

66

Potential

DNA binding

1245 – 1376

132

Potential

Zinc finger

1348 – 1374

27

C4-type

Compositional bias

75 – 112

38

Asp-rich

Compositional bias

1047 – 1050

4

Poly-Leu

Compositional bias

1051 – 1054

4

Poly-Lys

Sites

Site

124 – 125

2

Cleavage

Amino acid modifications

Modified residue

129

1

Phosphothreonine Ref.11

Modified residue

174

1

Phosphothreonine Ref.13

Modified residue

186

1

Phosphoserine Ref.10 Ref.13

Modified residue

190

1

Phosphoserine Ref.10

Modified residue

209

1

Phosphoserine Ref.9 Ref.10

Modified residue

219

1

Phosphothreonine Ref.11

Natural variations

Natural variant

740

1

Y → H.
Corresponds to variant rs2230927 [ dbSNP | Ensembl ].

VAR_048877

Experimental info

Sequence conflict

503 – 506

4

SPQL → KSTA in CAA29920. Ref.1

Sequence conflict

837

1

A → G in CAA29920. Ref.1

Sequence conflict

1405

1

L → C AA sequence Ref.4

Sequence conflict

1426

1

V → C AA sequence Ref.4

Secondary structure

1

.

.

.

.

.

1462

Helix Strand Turn

Details...

Helix

1346 – 1358

13

Beta strand

1366 – 1369

4

Sequences

	Sequence		Length	Mass (Da)
	P09884 [UniParc]. Last modified February 1, 2005. Version 2. Checksum: DC40C3EDD6F4B495	FASTA	1,462	165,913
	10 20 30 40 50 60 MAPVHGDDSL SDSGSFVSSR ARREKKSKKG RQEALERLKK AKAGEKYKYE VEDFTGVYEE 70 80 90 100 110 120 VDEEQYSKLV QARQDDDWIV DDDGIGYVED GREIFDDDLE DDALDADEKG KDGKARNKDK 130 140 150 160 170 180 RNVKKLAVTK PNNIKSMFIA CAGKKTADKA VDLSKDGLLG DILQDLNTET PQITPPPVMI 190 200 210 220 230 240 LKKKRSIGAS PNPFSVHTAT AVPSGKIASP VSRKEPPLTP VPLKRAEFAG DDVQVESTEE 250 260 270 280 290 300 EQESGAMEFE DGDFDEPMEV EEVDLEPMAA KAWDKESEPA EEVKQEADSG KGTVSYLGSF 310 320 330 340 350 360 LPDVSCWDID QEGDSSFSVQ EVQVDSSHLP LVKGADEEQV FHFYWLDAYE DQYNQPGVVF 370 380 390 400 410 420 LFGKVWIESA ETHVSCCVMV KNIERTLYFL PREMKIDLNT GKETGTPISM KDVYEEFDEK 430 440 450 460 470 480 IATKYKIMKF KSKPVEKNYA FEIPDVPEKS EYLEVKYSAE MPQLPQDLKG ETFSHVFGTN 490 500 510 520 530 540 TSSLELFLMN RKIKGPCWLE VKSPQLLNQP VSWCKVEAMA LKPDLVNVIK DVSPPPLVVM 550 560 570 580 590 600 AFSMKTMQNA KNHQNEIIAM AALVHHSFAL DKAAPKPPFQ SHFCVVSKPK DCIFPYAFKE 610 620 630 640 650 660 VIEKKNVKVE VAATERTLLG FFLAKVHKID PDIIVGHNIY GFELEVLLQR INVCKAPHWS 670 680 690 700 710 720 KIGRLKRSNM PKLGGRSGFG ERNATCGRMI CDVEISAKEL IRCKSYHLSE LVQQILKTER 730 740 750 760 770 780 VVIPMENIQN MYSESSQLLY LLEHTWKDAK FILQIMCELN VLPLALQITN IAGNIMSRTL 790 800 810 820 830 840 MGGRSERNEF LLLHAFYENN YIVPDKQIFR KPQQKLGDED EEIDGDTNKY KKGRKKAAYA 850 860 870 880 890 900 GGLVLDPKVG FYDKFILLLD FNSLYPSIIQ EFNICFTTVQ RVASEAQKVT EDGEQEQIPE 910 920 930 940 950 960 LPDPSLEMGI LPREIRKLVE RRKQVKQLMK QQDLNPDLIL QYDIRQKALK LTANSMYGCL 970 980 990 1000 1010 1020 GFSYSRFYAK PLAALVTYKG REILMHTKEM VQKMNLEVIY GDTDSIMINT NSTNLEEVFK 1030 1040 1050 1060 1070 1080 LGNKVKSEVN KLYKLLEIDI DGVFKSLLLL KKKKYAALVV EPTSDGNYVT KQELKGLDIV 1090 1100 1110 1120 1130 1140 RRDWCDLAKD TGNFVIGQIL SDQSRDTIVE NIQKRLIEIG ENVLNGSVPV SQFEINKALT 1150 1160 1170 1180 1190 1200 KDPQDYPDKK SLPHVHVALW INSQGGRKVK AGDTVSYVIC QDGSNLTASQ RAYAPEQLQK 1210 1220 1230 1240 1250 1260 QDNLTIDTQY YLAQQIHPVV ARICEPIDGI DAVLIATWLG LDPTQFRVHH YHKDEENDAL 1270 1280 1290 1300 1310 1320 LGGPAQLTDE EKYRDCERFK CPCPTCGTEN IYDNVFDGSG TDMEPSLYRC SNIDCKASPL 1330 1340 1350 1360 1370 1380 TFTVQLSNKL IMDIRRFIKK YYDGWLICEE PTCRNRTRHL PLQFSRTGPL CPACMKATLQ 1390 1400 1410 1420 1430 1440 PEYSDKSLYT QLCFYRYIFD AECALEKLTT DHEKDKLKKQ FFTPKVLQDY RKLKNTAEQF 1450 1460 LSRSGYSEVN LSKLFAGCAV KS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human DNA polymerase alpha gene expression is cell proliferation dependent and its primary structure is similar to both prokaryotic and eukaryotic replicative DNA polymerases." Wong S.W., Wahl A.F., Yuan P.-M., Arai N., Pearson B.E., Arai K., Korn D., Hunkapiller M.W., Wang T.S.-F. EMBO J. 7:37-47(1988) [PubMed: 3359994] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	NIEHS SNPs program Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Human DNA polymerase alpha gene: sequences controlling expression in cycling and serum-stimulated cells." Pearson B.E., Nasheuer H.-P., Wang T.S.-F. Mol. Cell. Biol. 11:2081-2095(1991) [PubMed: 2005899] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-8.
[4]	"Human DNA polymerase alpha catalytic polypeptide binds ConA and RCA and contains a specific labile site in the N-terminus." Hsi K.-L., Copeland W.C., Wang T.S.-F. Nucleic Acids Res. 18:6231-6237(1990) [PubMed: 2243771] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-37 AND 1405-1426, PROTEOLYTIC PROCESSING AT LYS-124.
[5]	"T-antigen-DNA polymerase alpha complex implicated in simian virus 40 DNA replication." Smale S.T., Tjian R. Mol. Cell. Biol. 6:4077-4087(1986) [PubMed: 3025630] [Abstract] Cited for: INTERACTION WITH SV40 LARGE T ANTIGEN.
[6]	"Interaction of herpes simplex virus 1 origin-binding protein with DNA polymerase alpha." Lee S.S., Dong Q., Wang T.S., Lehman I.R. Proc. Natl. Acad. Sci. U.S.A. 92:7882-7886(1995) [PubMed: 7644508] [Abstract] Cited for: INTERACTION WITH HHV-1 UL9 PROTEIN.
[7]	"Role of protein-protein interactions in the function of replication protein A (RPA): RPA modulates the activity of DNA polymerase alpha by multiple mechanisms." Braun K.A., Lao Y., He Z., Ingles C.J., Wold M.S. Biochemistry 36:8443-8454(1997) [PubMed: 9214288] [Abstract] Cited for: INTERACTION WITH RPA1.
[8]	"Functional association of poly(ADP-ribose) polymerase with DNA polymerase alpha-primase complex: a link between DNA strand break detection and DNA replication." Dantzer F., Nasheuer H.P., Vonesch J.L., de Murcia G., Menissier-de Murcia J. Nucleic Acids Res. 26:1891-1898(1998) [PubMed: 9518481] [Abstract] Cited for: FUNCTION, INTERACTION WITH PARP1.
[9]	"Evaluation of the low-specificity protease elastase for large-scale phosphoproteome analysis." Wang B., Malik R., Nigg E.A., Korner R. Anal. Chem. 80:9526-9533(2008) [PubMed: 19007248] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-209, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-186; SER-190 AND SER-209, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[11]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-129 AND THR-219, MASS SPECTROMETRY. Tissue: Embryonic kidney.
[12]	"Physical interactions between Mcm10, DNA, and DNA polymerase alpha." Warren E.M., Huang H., Fanning E., Chazin W.J., Eichman B.F. J. Biol. Chem. 284:24662-24672(2009) [PubMed: 19608746] [Abstract] Cited for: INTERACTION WITH MCM10.
[13]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed: 19690332] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-174 AND SER-186, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[14]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[15]	"Nuclear magnetic resonance structures of the zinc finger domain of human DNA polymerase-alpha." Evanics F., Maurmann L., Yang W.W., Bose R.N. Biochim. Biophys. Acta 1651:163-171(2003) [PubMed: 14499601] [Abstract] Cited for: STRUCTURE BY NMR OF 1345-1382.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X06745 mRNA. Translation: CAA29920.1.
AY275833 Genomic DNA. Translation: AAP13534.1.
M64481 Genomic DNA. Translation: AAA52318.1.

IPI

IPI00220317.

PIR

DJHUAC. S00257.

RefSeq

NP_058633.2. NM_016937.3.

UniGene

Hs.567319.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1K0P	NMR	-	A	1347-1377	[»]
1K18	NMR	-	A	1347-1377	[»]
1N5G	NMR	-	A	1345-1382	[»]

ProteinModelPortal

P09884.

SMR

P09884. Positions 337-1232, 1269-1444.

ModBase

Search...

Protein-protein interaction databases

IntAct

P09884. 5 interactions.

MINT

MINT-1517478.

STRING

P09884.

PTM databases

PhosphoSite

P09884.

Polymorphism databases

DMDM

60392197.

Proteomic databases

PRIDE

P09884.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000379059; ENSP00000368349; ENSG00000101868.

GeneID

5422.

KEGG

hsa:5422.

UCSC

uc004dbl.1. human.

Organism-specific databases

CTD

5422.

GeneCards

GC0XP024712.

H-InvDB

HIX0028476.

HGNC

HGNC:9173. POLA1.

HPA

CAB012274.
HPA002947.

MIM

312040. gene.

neXtProt

NX_P09884.

PharmGKB

PA162399856.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG18712.

GeneTree

ENSGT00550000074891.

HOVERGEN

HBG080008.

PhylomeDB

P09884.

Enzyme and pathway databases

Reactome

REACT_152. Cell Cycle, Mitotic.
REACT_22172. Chromosome Maintenance.
REACT_383. DNA Replication.

Gene expression databases

ArrayExpress

P09884.

Bgee

P09884.

CleanEx

HS_POLA1.

Genevestigator

P09884.

Family and domain databases

InterPro

IPR006172. DNA-dir_DNA_pol_B.
IPR017964. DNA-dir_DNA_pol_B_CS.
IPR006133. DNA-dir_DNA_pol_B_exonuc.
IPR006134. DNA-dir_DNA_pol_B_multi_dom.
IPR004578. DNA-dir_DNA_pol_B_pol2.
IPR024647. DNA_pol_a_cat_su_N.
IPR023211. DNA_pol_palm_dom.
IPR012337. RNaseH-like_dom.
IPR015088. Znf_DNA-dir_DNA_pol_B_alpha.
[Graphical view]

Gene3D

G3DSA:3.90.1600.10. DNA_pol_palm_dom. 2 hits.

KO

K02320.

Pfam

PF12254. DNA_pol_alpha_N. 1 hit.
PF00136. DNA_pol_B. 1 hit.
PF03104. DNA_pol_B_exo1. 1 hit.
PF08996. zf-DNA_Pol. 1 hit.
[Graphical view]

PRINTS

PR00106. DNAPOLB.

SMART

SM00486. POLBc. 1 hit.
[Graphical view]

SUPFAM

SSF53098. RNaseH_fold. 1 hit.

TIGRFAMs

TIGR00592. Pol2. 1 hit.

PROSITE

PS00116. DNA_POLYMERASE_B. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB00631. Clofarabine.
DB01073. Fludarabine.

NextBio

20977.

SOURCE

Search...

Entry information

Entry name

DPOLA_HUMAN

Accession

Primary (citable) accession number: P09884
Secondary accession number(s): Q86UQ7

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 1, 1989
Last sequence update:	February 1, 2005
Last modified:	January 25, 2012
This is version 125 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.