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DNA polymerase delta catalytic subunit (EC 2.7.7.7) (EC 3.1.11.-) (DNA polymerase subunit delta p125)

 DPOD1_HUMAN             Reviewed;        1107 AA.
P28340; Q8NER3; Q96H98;
01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
19-JUL-2004, sequence version 2.
30-AUG-2017, entry version 181.
RecName: Full=DNA polymerase delta catalytic subunit;
EC=2.7.7.7;
EC=3.1.11.-;
AltName: Full=DNA polymerase subunit delta p125;
Name=POLD1; Synonyms=POLD;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT TRP-30.
TISSUE=Hepatoma;
PubMed=1722322; DOI=10.1073/pnas.88.24.11197;
Chung D.W., Zhang J., Tan C.-K., Davie E.W., So A.G., Downey K.M.;
"Primary structure of the catalytic subunit of human DNA polymerase
delta and chromosomal location of the gene.";
Proc. Natl. Acad. Sci. U.S.A. 88:11197-11201(1991).
[2]
NUCLEOTIDE SEQUENCE [MRNA], VARIANTS HIS-119 AND ASN-173, AND
INDUCTION BY SERUM.
TISSUE=Cervix carcinoma;
PubMed=1542570; DOI=10.1093/nar/20.4.735;
Yang C.-L., Chang L.-S., Zhang P., Hao H., Zhu L., Toomey N.L.,
Lee M.Y.W.T.;
"Molecular cloning of the cDNA for the catalytic subunit of human DNA
polymerase delta.";
Nucleic Acids Res. 20:735-745(1992).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-19; TRP-30;
HIS-119; ASN-173; HIS-177; HIS-849 AND GLN-1086.
NIEHS SNPs program;
Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-119.
TISSUE=Lymph;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[5]
INTERACTION WITH POLD2 AND PCNA.
PubMed=11328591; DOI=10.1093/oxfordjournals.jbchem.a002909;
Shikata K., Ohta S., Yamada K., Obuse C., Yoshikawa H., Tsurimoto T.;
"The human homologue of fission Yeast cdc27, p66, is a component of
active human DNA polymerase delta.";
J. Biochem. 129:699-708(2001).
[6]
INTERACTION WITH POLD3, AND SUBCELLULAR LOCATION.
PubMed=11595739; DOI=10.1074/jbc.M106990200;
Ducoux M., Urbach S., Baldacci G., Huebscher U., Koundrioukoff S.,
Christensen J., Hughes P.;
"Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA
replication through a conserved p21(Cip1)-like PCNA-binding motif
present in the third subunit of human DNA polymerase delta.";
J. Biol. Chem. 276:49258-49266(2001).
[7]
INTERACTION WITH PCNA AND POLD4, AND CHARACTERIZATION OF POL-DELTA2
AND POL-DELTA4 COMPLEXES.
PubMed=12403614; DOI=10.1021/bi0262707;
Xie B., Mazloum N., Liu L., Rahmeh A., Li H., Lee M.Y.;
"Reconstitution and characterization of the human DNA polymerase delta
four-subunit holoenzyme.";
Biochemistry 41:13133-13142(2002).
[8]
INTERACTION WITH POLD2 AND POLDIP2, AND STIMULATION BY PCNA.
PubMed=12522211; DOI=10.1074/jbc.M208694200;
Liu L., Rodriguez-Belmonte E.M., Mazloum N., Xie B., Lee M.Y.W.T.;
"Identification of a novel protein, PDIP38, that interacts with the
p50 subunit of DNA polymerase delta and proliferating cell nuclear
antigen.";
J. Biol. Chem. 278:10041-10047(2003).
[9]
INTERACTION WITH WRNIP1.
PubMed=15670210; DOI=10.1111/j.1365-2443.2004.00812.x;
Tsurimoto T., Shinozaki A., Yano M., Seki M., Enomoto T.;
"Human Werner helicase interacting protein 1 (WRNIP1) functions as a
novel modulator for DNA polymerase delta.";
Genes Cells 10:13-22(2005).
[10]
FUNCTION, AND INTERACTION WITH POLD2; POLD4 AND PCNA.
PubMed=16510448; DOI=10.1074/jbc.M600322200;
Li H., Xie B., Zhou Y., Rahmeh A., Trusa S., Zhang S., Gao Y.,
Lee E.Y., Lee M.Y.;
"Functional roles of p12, the fourth subunit of human DNA polymerase
delta.";
J. Biol. Chem. 281:14748-14755(2006).
[11]
IDENTIFICATION IN POL-DELTA COMPLEX.
PubMed=17317665; DOI=10.1074/jbc.M610356200;
Zhang S., Zhou Y., Trusa S., Meng X., Lee E.Y., Lee M.Y.;
"A novel DNA damage response: rapid degradation of the p12 subunit of
dna polymerase delta.";
J. Biol. Chem. 282:15330-15340(2007).
[12]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Cervix carcinoma;
PubMed=18669648; DOI=10.1073/pnas.0805139105;
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
Elledge S.J., Gygi S.P.;
"A quantitative atlas of mitotic phosphorylation.";
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
[13]
FUNCTION, MUTAGENESIS OF ASP-402, CHARACTERIZATION OF POL-DELTA3 AND
POL-DELTA4, AND ENZYME REGULATION.
PubMed=19074196; DOI=10.1093/nar/gkn1000;
Meng X., Zhou Y., Zhang S., Lee E.Y., Frick D.N., Lee M.Y.;
"DNA damage alters DNA polymerase delta to a form that exhibits
increased discrimination against modified template bases and
mismatched primers.";
Nucleic Acids Res. 37:647-657(2009).
[14]
FUNCTION, CHARACTERIZATION OF POL-DELTA3 AND POL-DELTA4,
BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ASP-402.
PubMed=20334433; DOI=10.1021/bi100042b;
Meng X., Zhou Y., Lee E.Y., Lee M.Y., Frick D.N.;
"The p12 subunit of human polymerase delta modulates the rate and
fidelity of DNA synthesis.";
Biochemistry 49:3545-3554(2010).
[15]
FUNCTION IN NUCLEOTIDE EXCISION REPAIR, AND SUBCELLULAR LOCATION.
PubMed=20227374; DOI=10.1016/j.molcel.2010.02.009;
Ogi T., Limsirichaikul S., Overmeer R.M., Volker M., Takenaka K.,
Cloney R., Nakazawa Y., Niimi A., Miki Y., Jaspers N.G.,
Mullenders L.H., Yamashita S., Fousteri M.I., Lehmann A.R.;
"Three DNA polymerases, recruited by different mechanisms, carry out
NER repair synthesis in human cells.";
Mol. Cell 37:714-727(2010).
[16]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21269460; DOI=10.1186/1752-0509-5-17;
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
"Initial characterization of the human central proteome.";
BMC Syst. Biol. 5:17-17(2011).
[17]
SUBCELLULAR LOCATION, IDENTIFICATION IN POLD COMPLEX, AND
DEVELOPMENTAL STAGE.
PubMed=22801543; DOI=10.4161/cc.21280;
Chea J., Zhang S., Zhao H., Zhang Z., Lee E.Y., Darzynkiewicz Z.,
Lee M.Y.;
"Spatiotemporal recruitment of human DNA polymerase delta to sites of
UV damage.";
Cell Cycle 11:2885-2895(2012).
[18]
FUNCTION IN OKAZAKI FRAGMENT PROCESSING.
PubMed=24035200; DOI=10.1016/j.dnarep.2013.08.008;
Lin S.H., Wang X., Zhang S., Zhang Z., Lee E.Y., Lee M.Y.;
"Dynamics of enzymatic interactions during short flap human Okazaki
fragment processing by two forms of human DNA polymerase delta.";
DNA Repair 12:922-935(2013).
[19]
POL-DELTA3 COMPLEX EXPRESSION DURING CELL CYCLE.
PubMed=23913683; DOI=10.1074/jbc.M113.490466;
Zhang S., Zhao H., Darzynkiewicz Z., Zhou P., Zhang Z., Lee E.Y.,
Lee M.Y.;
"A novel function of CRL4(Cdt2): regulation of the subunit structure
of DNA polymerase delta in response to DNA damage and during the S
phase.";
J. Biol. Chem. 288:29550-29561(2013).
[20]
FUNCTION, AND INTERACTION WITH PCNA.
PubMed=24022480; DOI=10.1074/jbc.C113.505586;
Terai K., Shibata E., Abbas T., Dutta A.;
"Degradation of p12 subunit by CRL4Cdt2 E3 ligase inhibits fork
progression after DNA damage.";
J. Biol. Chem. 288:30509-30514(2013).
[21]
TISSUE SPECIFICITY, AND VARIANT MDPL SER-605 DEL.
PubMed=23770608; DOI=10.1038/ng.2670;
Weedon M.N., Ellard S., Prindle M.J., Caswell R., Allen H.L., Oram R.,
Godbole K., Yajnik C.S., Sbraccia P., Novelli G., Turnpenny P.,
McCann E., Goh K.J., Wang Y., Fulford J., McCulloch L.J., Savage D.B.,
O'Rahilly S., Kos K., Loeb L.A., Semple R.K., Hattersley A.T.;
"An in-frame deletion at the polymerase active site of POLD1 causes a
multisystem disorder with lipodystrophy.";
Nat. Genet. 45:947-950(2013).
[22]
METHYLATION [LARGE SCALE ANALYSIS] AT ARG-19, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Colon carcinoma;
PubMed=24129315; DOI=10.1074/mcp.O113.027870;
Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V.,
Aguiar M., Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C.,
Vemulapalli V., Bedford M.T., Comb M.J.;
"Immunoaffinity enrichment and mass spectrometry analysis of protein
methylation.";
Mol. Cell. Proteomics 13:372-387(2014).
[23]
INTERACTION WITH PCNA.
PubMed=24939902; DOI=10.1093/nar/gku533;
Cazzalini O., Sommatis S., Tillhon M., Dutto I., Bachi A., Rapp A.,
Nardo T., Scovassi A.I., Necchi D., Cardoso M.C., Stivala L.A.,
Prosperi E.;
"CBP and p300 acetylate PCNA to link its degradation with nucleotide
excision repair synthesis.";
Nucleic Acids Res. 42:8433-8448(2014).
[24]
FUNCTION IN BIR.
PubMed=24310611; DOI=10.1126/science.1243211;
Costantino L., Sotiriou S.K., Rantala J.K., Magin S., Mladenov E.,
Helleday T., Haber J.E., Iliakis G., Kallioniemi O.P.,
Halazonetis T.D.;
"Break-induced replication repair of damaged forks induces genomic
duplications in human cells.";
Science 343:88-91(2014).
[25]
SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-574, AND IDENTIFICATION BY
MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=28112733; DOI=10.1038/nsmb.3366;
Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
Nielsen M.L.;
"Site-specific mapping of the human SUMO proteome reveals co-
modification with phosphorylation.";
Nat. Struct. Mol. Biol. 24:325-336(2017).
[26]
VARIANT CRCS10 ASN-478, AND VARIANTS ASP-145; HIS-461; LEU-787;
HIS-808 AND THR-864.
PubMed=23263490; DOI=10.1038/ng.2503;
CORGI Consortium;
WGS500 Consortium;
Palles C., Cazier J.B., Howarth K.M., Domingo E., Jones A.M.,
Broderick P., Kemp Z., Spain S.L., Guarino Almeida E., Salguero I.,
Sherborne A., Chubb D., Carvajal-Carmona L.G., Ma Y., Kaur K.,
Dobbins S., Barclay E., Gorman M., Martin L., Kovac M.B., Humphray S.,
Lucassen A., Holmes C.C., Bentley D., Donnelly P., Taylor J.,
Petridis C., Roylance R., Sawyer E.J., Kerr D.J., Clark S., Grimes J.,
Kearsey S.E., Thomas H.J., McVean G., Houlston R.S., Tomlinson I.;
"Germline mutations affecting the proofreading domains of POLE and
POLD1 predispose to colorectal adenomas and carcinomas.";
Nat. Genet. 45:136-144(2013).
[27]
VARIANT CRCS10 PRO-474.
PubMed=24501277; DOI=10.1093/hmg/ddu058;
Valle L., Hernandez-Illan E., Bellido F., Aiza G., Castillejo A.,
Castillejo M.I., Navarro M., Segui N., Vargas G., Guarinos C.,
Juarez M., Sanjuan X., Iglesias S., Alenda C., Egoavil C., Segura A.,
Juan M.J., Rodriguez-Soler M., Brunet J., Gonzalez S., Jover R.,
Lazaro C., Capella G., Pineda M., Soto J.L., Blanco I.;
"New insights into POLE and POLD1 germline mutations in familial
colorectal cancer and polyposis.";
Hum. Mol. Genet. 23:3506-3512(2014).
-!- FUNCTION: As the catalytic component of the trimeric (Pol-delta3
complex) and tetrameric DNA polymerase delta complexes (Pol-delta4
complex), plays a crucial role in high fidelity genome
replication, including in lagging strand synthesis, and repair.
Exhibits both DNA polymerase and 3'- to 5'-exonuclease activities
(PubMed:16510448, PubMed:19074196, PubMed:20334433,
PubMed:24035200, PubMed:24022480). Requires the presence of
accessory proteins POLD2, POLD3 and POLD4 for full activity.
Depending upon the absence (Pol-delta3) or the presence of POLD4
(Pol-delta4), displays differences in catalytic activity. Most
notably, expresses higher proofreading activity in the context of
Pol-delta3 compared with that of Pol-delta4 (PubMed:19074196,
PubMed:20334433). Although both Pol-delta3 and Pol-delta4 process
Okazaki fragments in vitro, Pol-delta3 may be better suited to
fulfill this task, exhibiting near-absence of strand displacement
activity compared to Pol-delta4 and stalling on encounter with the
5'-blocking oligonucleotides. Pol-delta3 idling process may avoid
the formation of a gap, while maintaining a nick that can be
readily ligated (PubMed:24035200). Along with DNA polymerase
kappa, DNA polymerase delta carries out approximately half of
nucleotide excision repair (NER) synthesis following UV
irradiation (PubMed:20227374). Under conditions of DNA replication
stress, in the presence of POLD3 and POLD4, may catalyze the
repair of broken replication forks through break-induced
replication (BIR) (PubMed:24310611). Involved in the translesion
synthesis (TLS) of templates carrying O6-methylguanine or abasic
sites (PubMed:19074196). {ECO:0000269|PubMed:16510448,
ECO:0000269|PubMed:19074196, ECO:0000269|PubMed:20227374,
ECO:0000269|PubMed:20334433, ECO:0000269|PubMed:24022480,
ECO:0000269|PubMed:24035200, ECO:0000269|PubMed:24310611}.
-!- CATALYTIC ACTIVITY: Deoxynucleoside triphosphate + DNA(n) =
diphosphate + DNA(n+1).
-!- COFACTOR:
Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883;
Evidence={ECO:0000250};
Note=Binds 1 [4Fe-4S] cluster. {ECO:0000250};
-!- ENZYME REGULATION: Regulated by alteration of quaternary
structure. Exhibits burst rates of DNA synthesis are about 5 times
faster in the presence of POLD4 (Pol-delta4 complex) than in its
absence (Pol-delta3 complex), while the affinity of the enzyme for
its DNA and dNTP substrates appears unchanged. The Pol-delta3
complex is more likely to proofread DNA synthesis because it
cleaves single-stranded DNA twice as fast and transfers mismatched
DNA from the polymerase to the exonuclease sites 9 times faster
compared to the Pol-delta3 complex. Pol-delta3 also extends
mismatched primers 3 times more slowly in the absence of POLD4.
The conversion of Pol-delta4 into Pol-delta3 is induced by
genotoxic stress or by replication stress leading POLD4
degradation (PubMed:19074196, PubMed:20334433). Stimulated in the
presence of PCNA (PubMed:11328591, PubMed:12403614,
PubMed:12522211, PubMed:16510448, PubMed:24022480,
PubMed:24939902). This stimulation is further increased in the
presence of KCTD13/PDIP1, most probably via direct interaction
between KCTD13 and POLD2 (By similarity).
{ECO:0000250|UniProtKB:P28339, ECO:0000269|PubMed:11328591,
ECO:0000269|PubMed:12403614, ECO:0000269|PubMed:12522211,
ECO:0000269|PubMed:16510448, ECO:0000269|PubMed:19074196,
ECO:0000269|PubMed:20334433, ECO:0000269|PubMed:24022480,
ECO:0000269|PubMed:24939902}.
-!- BIOPHYSICOCHEMICAL PROPERTIES:
Kinetic parameters:
Note=kcat is 87 sec(-1) for DNA synthesis by Pol-delta4 and 19
sec(-1) for Pol-delta3. kcat for exonuclease activity determined
using a 26mer/40mer duplex DNA gives a value of 0.003 sec(-1)
for Pol-delta4 and 0.026 sec(-1) for Pol-delta3. When using a
26mer/40mer with a T:G mismatch at the primer terminus, the
switching rates from the polymerase to the exonuclease site for
Pol-delta4 and Pol-delta3 are increased 20- and 10-fold,
respectively, but the rate constant for Pol-delta3 is still 5-
fold faster than that for Pol-delta4.;
-!- SUBUNIT: Component of the tetrameric DNA polymerase delta complex
(Pol-delta4), which consists of POLD1/p125, POLD2/p50,
POLD3/p66/p68 and POLD4/p12, with POLD1 bearing both DNA
polymerase and 3' to 5' proofreading exonuclease activities
(PubMed:11595739, PubMed:12522211, PubMed:17317665,
PubMed:22801543). Within Pol-delta4, directly interacts with POLD2
and POLD4 (PubMed:11328591, PubMed:12403614, PubMed:16510448).
Following genotoxic stress by DNA-damaging agents, such as
ultraviolet light and methyl methanesulfonate, or by replication
stress induced by treatment with hydroxyurea or aphidicolin, Pol-
delta4 is converted into a trimeric form of the complex (Pol-
delta3) by POLD4 degradation. Pol-delta3 is the major form at S
phase replication sites and DNA damage sites (PubMed:22801543,
PubMed:17317665). POLD1 displays different catalytic properties
depending upon the complex it is found in (PubMed:17317665). It
exhibits higher proofreading activity and fidelity than Pol-
delta4, making it particularly well suited to respond to DNA
damage (PubMed:19074196, PubMed:20334433). Directly interacts with
PCNA, as do POLD3 and POLD4; this interaction stimulates Pol-
delta4 polymerase activity (PubMed:11328591, PubMed:12403614,
PubMed:12522211, PubMed:16510448, PubMed:24022480,
PubMed:24939902). As POLD2 and POLD4, directly interacts with
WRNIP1; this interaction stimulates DNA polymerase delta-mediated
DNA synthesis, independently of the presence of PCNA. This
stimulation may be due predominantly to an increase of initiation
frequency and also to increased processivity (PubMed:15670210).
Also observed as a dimeric complex with POLD2 (Pol-delta2
complex). Pol-delta2 is relatively insensitive to the PCNA
stimulation (2-5-fold) compared to Pol-delta4 that is stimulated
by over 50-fold (PubMed:12403614). The DNA polymerase delta
complex interacts with POLDIP2; this interaction is probably
mediated through direct binding to POLD2 (PubMed:12522211).
{ECO:0000269|PubMed:11328591, ECO:0000269|PubMed:11595739,
ECO:0000269|PubMed:12403614, ECO:0000269|PubMed:12522211,
ECO:0000269|PubMed:15670210, ECO:0000269|PubMed:16510448,
ECO:0000269|PubMed:17317665, ECO:0000269|PubMed:19074196,
ECO:0000269|PubMed:20334433, ECO:0000269|PubMed:22801543,
ECO:0000269|PubMed:24022480, ECO:0000269|PubMed:24939902}.
-!- INTERACTION:
P12004:PCNA; NbExp=3; IntAct=EBI-716569, EBI-358311;
P49005:POLD2; NbExp=10; IntAct=EBI-716569, EBI-372354;
Q9HCU8:POLD4; NbExp=11; IntAct=EBI-716569, EBI-864968;
Q9NYB0:TERF2IP; NbExp=2; IntAct=EBI-716569, EBI-750109;
Q96S55:WRNIP1; NbExp=2; IntAct=EBI-716569, EBI-2513471;
-!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11595739,
ECO:0000269|PubMed:20227374, ECO:0000269|PubMed:22801543}.
Note=Colocalizes with PCNA and POLD3 at S phase replication sites
(PubMed:11595739). After UV irradiation, recruited to DNA damage
sites within 2 hours, independently on the cell cycle phase, nor
on PCNA ubiquitination. This recruitement requires POLD3, PCNA and
RFC1-replication factor C complex (PubMed:20227374,
PubMed:22801543). {ECO:0000269|PubMed:11595739,
ECO:0000269|PubMed:20227374, ECO:0000269|PubMed:22801543}.
-!- TISSUE SPECIFICITY: Widely expressed, with high levels of
expression in heart and lung. {ECO:0000269|PubMed:23770608}.
-!- DEVELOPMENTAL STAGE: Expression is cell cycle-dependent, with
highest levels in G2/M phase and lowest in G1.
{ECO:0000269|PubMed:22801543}.
-!- INDUCTION: Up-regulated by serum stimulation.
{ECO:0000269|PubMed:1542570}.
-!- DOMAIN: The CysB motif binds 1 4Fe-4S cluster and is required for
the formation of polymerase complexes. {ECO:0000250}.
-!- DISEASE: Colorectal cancer 10 (CRCS10) [MIM:612591]: A complex
disease characterized by malignant lesions arising from the inner
wall of the large intestine (the colon) and the rectum. Genetic
alterations are often associated with progression from
premalignant lesion (adenoma) to invasive adenocarcinoma. Risk
factors for cancer of the colon and rectum include colon polyps,
long-standing ulcerative colitis, and genetic family history.
{ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24501277}.
Note=Disease susceptibility is associated with variations
affecting the gene represented in this entry.
-!- DISEASE: Mandibular hypoplasia, deafness, progeroid features, and
lipodystrophy syndrome (MDPL) [MIM:615381]: An autosomal dominant
systemic disorder characterized by prominent loss of subcutaneous
fat, metabolic abnormalities including insulin resistance and
diabetes mellitus, sclerodermatous skin, and a facial appearance
characterized by mandibular hypoplasia. Sensorineural deafness
occurs late in the first or second decades of life.
{ECO:0000269|PubMed:23770608}. Note=The disease is caused by
mutations affecting the gene represented in this entry.
-!- SIMILARITY: Belongs to the DNA polymerase type-B family.
{ECO:0000305}.
-!- WEB RESOURCE: Name=NIEHS-SNPs;
URL="http://egp.gs.washington.edu/data/pold1/";
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EMBL; M80397; AAA58439.1; -; mRNA.
EMBL; M81735; AAA35768.1; -; mRNA.
EMBL; AY129569; AAM76971.1; -; Genomic_DNA.
EMBL; BC008800; AAH08800.1; -; mRNA.
CCDS; CCDS12795.1; -.
PIR; A41618; A41618.
RefSeq; NP_001243778.1; NM_001256849.1.
RefSeq; NP_002682.2; NM_002691.3.
RefSeq; XP_011525340.1; XM_011527038.1.
RefSeq; XP_016882370.1; XM_017026881.1.
UniGene; Hs.279413; -.
ProteinModelPortal; P28340; -.
SMR; P28340; -.
BioGrid; 111420; 68.
IntAct; P28340; 36.
MINT; MINT-1414678; -.
STRING; 9606.ENSP00000406046; -.
BindingDB; P28340; -.
ChEMBL; CHEMBL2735; -.
iPTMnet; P28340; -.
PhosphoSitePlus; P28340; -.
BioMuta; POLD1; -.
DMDM; 50403732; -.
EPD; P28340; -.
MaxQB; P28340; -.
PaxDb; P28340; -.
PeptideAtlas; P28340; -.
PRIDE; P28340; -.
DNASU; 5424; -.
Ensembl; ENST00000440232; ENSP00000406046; ENSG00000062822.
Ensembl; ENST00000599857; ENSP00000473052; ENSG00000062822.
GeneID; 5424; -.
KEGG; hsa:5424; -.
UCSC; uc002psb.6; human.
CTD; 5424; -.
DisGeNET; 5424; -.
GeneCards; POLD1; -.
H-InvDB; HIX0202825; -.
HGNC; HGNC:9175; POLD1.
HPA; CAB004375; -.
HPA; HPA046524; -.
MalaCards; POLD1; -.
MIM; 174761; gene.
MIM; 612591; phenotype.
MIM; 615381; phenotype.
neXtProt; NX_P28340; -.
OpenTargets; ENSG00000062822; -.
Orphanet; 363649; Mandibular hypoplasia-deafness-progeroid syndrome.
PharmGKB; PA33496; -.
eggNOG; KOG0968; Eukaryota.
eggNOG; COG0417; LUCA.
GeneTree; ENSGT00560000077365; -.
HOGENOM; HOG000036616; -.
HOVERGEN; HBG051395; -.
InParanoid; P28340; -.
KO; K02327; -.
PhylomeDB; P28340; -.
TreeFam; TF352785; -.
BRENDA; 2.7.7.7; 2681.
Reactome; R-HSA-110314; Recognition of DNA damage by PCNA-containing replication complex.
Reactome; R-HSA-174411; Polymerase switching on the C-strand of the telomere.
Reactome; R-HSA-174414; Processive synthesis on the C-strand of the telomere.
Reactome; R-HSA-174417; Telomere C-strand (Lagging Strand) Synthesis.
Reactome; R-HSA-174437; Removal of the Flap Intermediate from the C-strand.
Reactome; R-HSA-2564830; Cytosolic iron-sulfur cluster assembly.
Reactome; R-HSA-5358565; Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
Reactome; R-HSA-5358606; Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).
Reactome; R-HSA-5651801; PCNA-Dependent Long Patch Base Excision Repair.
Reactome; R-HSA-5656169; Termination of translesion DNA synthesis.
Reactome; R-HSA-5685942; HDR through Homologous Recombination (HRR).
Reactome; R-HSA-5696397; Gap-filling DNA repair synthesis and ligation in GG-NER.
Reactome; R-HSA-5696400; Dual Incision in GG-NER.
Reactome; R-HSA-6782135; Dual incision in TC-NER.
Reactome; R-HSA-6782210; Gap-filling DNA repair synthesis and ligation in TC-NER.
Reactome; R-HSA-69091; Polymerase switching.
Reactome; R-HSA-69166; Removal of the Flap Intermediate.
Reactome; R-HSA-69183; Processive synthesis on the lagging strand.
GeneWiki; POLD1; -.
GenomeRNAi; 5424; -.
PMAP-CutDB; P28340; -.
PRO; PR:P28340; -.
Proteomes; UP000005640; Chromosome 19.
Bgee; ENSG00000062822; -.
CleanEx; HS_POLD1; -.
ExpressionAtlas; P28340; baseline and differential.
Genevisible; P28340; HS.
GO; GO:0016235; C:aggresome; IDA:HPA.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0043625; C:delta DNA polymerase complex; IBA:GO_Central.
GO; GO:0016020; C:membrane; IDA:UniProtKB.
GO; GO:0005654; C:nucleoplasm; IDA:HPA.
GO; GO:0000109; C:nucleotide-excision repair complex; IDA:UniProtKB.
GO; GO:0005634; C:nucleus; IDA:UniProtKB.
GO; GO:0008296; F:3'-5'-exodeoxyribonuclease activity; IBA:GO_Central.
GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IEA:UniProtKB-KW.
GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
GO; GO:0003684; F:damaged DNA binding; IDA:UniProtKB.
GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
GO; GO:0003887; F:DNA-directed DNA polymerase activity; IMP:UniProtKB.
GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
GO; GO:0006287; P:base-excision repair, gap-filling; IDA:UniProtKB.
GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB.
GO; GO:0042769; P:DNA damage response, detection of DNA damage; TAS:Reactome.
GO; GO:0006266; P:DNA ligation; TAS:Reactome.
GO; GO:0006281; P:DNA repair; TAS:ProtInc.
GO; GO:0006260; P:DNA replication; IMP:UniProtKB.
GO; GO:0045004; P:DNA replication proofreading; IBA:GO_Central.
GO; GO:0000731; P:DNA synthesis involved in DNA repair; IDA:UniProtKB.
GO; GO:0055089; P:fatty acid homeostasis; IMP:UniProtKB.
GO; GO:0006298; P:mismatch repair; TAS:Reactome.
GO; GO:0006297; P:nucleotide-excision repair, DNA gap filling; IMP:UniProtKB.
GO; GO:0033683; P:nucleotide-excision repair, DNA incision; TAS:Reactome.
GO; GO:0006296; P:nucleotide-excision repair, DNA incision, 5'-to lesion; TAS:Reactome.
GO; GO:0009411; P:response to UV; TAS:ProtInc.
GO; GO:0000723; P:telomere maintenance; TAS:Reactome.
GO; GO:0000722; P:telomere maintenance via recombination; TAS:Reactome.
GO; GO:0006283; P:transcription-coupled nucleotide-excision repair; TAS:Reactome.
GO; GO:0019985; P:translesion synthesis; TAS:Reactome.
Gene3D; 3.30.420.10; -; 1.
Gene3D; 3.90.1600.10; -; 1.
InterPro; IPR006172; DNA-dir_DNA_pol_B.
InterPro; IPR017964; DNA-dir_DNA_pol_B_CS.
InterPro; IPR006133; DNA-dir_DNA_pol_B_exonuc.
InterPro; IPR006134; DNA-dir_DNA_pol_B_multi_dom.
InterPro; IPR023211; DNA_pol_palm_dom.
InterPro; IPR012337; RNaseH-like_dom.
InterPro; IPR025687; Znf-C4pol.
Pfam; PF00136; DNA_pol_B; 1.
Pfam; PF03104; DNA_pol_B_exo1; 1.
Pfam; PF14260; zf-C4pol; 1.
PRINTS; PR00106; DNAPOLB.
SMART; SM00486; POLBc; 1.
SUPFAM; SSF53098; SSF53098; 1.
PROSITE; PS00116; DNA_POLYMERASE_B; 1.
1: Evidence at protein level;
4Fe-4S; Complete proteome; Disease mutation; DNA damage; DNA excision;
DNA repair; DNA replication; DNA-binding; DNA-directed DNA polymerase;
Exonuclease; Hydrolase; Iron; Iron-sulfur; Isopeptide bond;
Metal-binding; Methylation; Nuclease; Nucleotidyltransferase; Nucleus;
Polymorphism; Reference proteome; Transferase; Ubl conjugation; Zinc;
Zinc-finger.
CHAIN 1 1107 DNA polymerase delta catalytic subunit.
/FTId=PRO_0000046442.
ZN_FING 1012 1029 CysA-type.
MOTIF 4 19 Nuclear localization signal.
{ECO:0000255}.
MOTIF 1058 1076 CysB motif.
METAL 1012 1012 Zinc. {ECO:0000250}.
METAL 1015 1015 Zinc. {ECO:0000250}.
METAL 1026 1026 Zinc. {ECO:0000250}.
METAL 1029 1029 Zinc. {ECO:0000250}.
METAL 1058 1058 Iron-sulfur (4Fe-4S). {ECO:0000250}.
METAL 1061 1061 Iron-sulfur (4Fe-4S). {ECO:0000250}.
METAL 1071 1071 Iron-sulfur (4Fe-4S). {ECO:0000250}.
METAL 1076 1076 Iron-sulfur (4Fe-4S). {ECO:0000250}.
MOD_RES 19 19 Omega-N-methylarginine.
{ECO:0000244|PubMed:24129315}.
CROSSLNK 574 574 Glycyl lysine isopeptide (Lys-Gly)
(interchain with G-Cter in SUMO2).
{ECO:0000244|PubMed:28112733}.
VARIANT 5 5 R -> W (in dbSNP:rs9282830).
/FTId=VAR_048878.
VARIANT 19 19 R -> H (in dbSNP:rs3218773).
{ECO:0000269|Ref.3}.
/FTId=VAR_019340.
VARIANT 21 21 G -> C (in dbSNP:rs9282831).
/FTId=VAR_048879.
VARIANT 30 30 R -> W (in dbSNP:rs3218772).
{ECO:0000269|PubMed:1722322,
ECO:0000269|Ref.3}.
/FTId=VAR_016146.
VARIANT 119 119 R -> H (in dbSNP:rs1726801).
{ECO:0000269|PubMed:1542570,
ECO:0000269|PubMed:15489334,
ECO:0000269|Ref.3}.
/FTId=VAR_019341.
VARIANT 145 145 A -> D (found in a colorectal sample;
somatic mutation).
{ECO:0000269|PubMed:23263490}.
/FTId=VAR_069333.
VARIANT 173 173 S -> N (in dbSNP:rs1726803).
{ECO:0000269|PubMed:1542570,
ECO:0000269|Ref.3}.
/FTId=VAR_019342.
VARIANT 177 177 R -> H (in dbSNP:rs3218750).
{ECO:0000269|Ref.3}.
/FTId=VAR_019343.
VARIANT 347 347 P -> L (in dbSNP:rs2230243).
/FTId=VAR_048880.
VARIANT 461 461 Q -> H (found in a colorectal sample;
somatic mutation).
{ECO:0000269|PubMed:23263490}.
/FTId=VAR_069334.
VARIANT 474 474 L -> P (in CRCS10; dbSNP:rs587777627).
{ECO:0000269|PubMed:24501277}.
/FTId=VAR_071966.
VARIANT 478 478 S -> N (in CRCS10; associated with
disease susceptibility;
dbSNP:rs397514632).
{ECO:0000269|PubMed:23263490}.
/FTId=VAR_069335.
VARIANT 605 605 Missing (in MDPL; the mutant enzyme lacks
DNA polymerase ability; has decreased
exonuclease activity; can bind DNA but is
unable to interact with and incorporate
dNTPs). {ECO:0000269|PubMed:23770608}.
/FTId=VAR_070231.
VARIANT 787 787 P -> L (found in a colorectal sample;
somatic mutation; dbSNP:rs199783227).
{ECO:0000269|PubMed:23263490}.
/FTId=VAR_069336.
VARIANT 808 808 R -> H (found in a colorectal sample;
somatic mutation; dbSNP:rs771700024).
{ECO:0000269|PubMed:23263490}.
/FTId=VAR_069337.
VARIANT 849 849 R -> H (in dbSNP:rs3218775).
{ECO:0000269|Ref.3}.
/FTId=VAR_019344.
VARIANT 864 864 A -> T (found in a colorectal sample;
somatic mutation).
{ECO:0000269|PubMed:23263490}.
/FTId=VAR_069338.
VARIANT 1086 1086 R -> Q (in dbSNP:rs3219457).
{ECO:0000269|Ref.3}.
/FTId=VAR_019345.
MUTAGEN 402 402 D->A: Loss of exonuclease activity. No
effect on DNA polymerase activity.
{ECO:0000269|PubMed:19074196,
ECO:0000269|PubMed:20334433}.
CONFLICT 472 472 Y -> H (in Ref. 1; AAA58439).
{ECO:0000305}.
CONFLICT 776 776 R -> G (in Ref. 2; AAA35768).
{ECO:0000305}.
SEQUENCE 1107 AA; 123631 MW; 9D04D34AB4AEE810 CRC64;
MDGKRRPGPG PGVPPKRARG GLWDDDDAPR PSQFEEDLAL MEEMEAEHRL QEQEEEELQS
VLEGVADGQV PPSAIDPRWL RPTPPALDPQ TEPLIFQQLE IDHYVGPAQP VPGGPPPSRG
SVPVLRAFGV TDEGFSVCCH IHGFAPYFYT PAPPGFGPEH MGDLQRELNL AISRDSRGGR
ELTGPAVLAV ELCSRESMFG YHGHGPSPFL RITVALPRLV APARRLLEQG IRVAGLGTPS
FAPYEANVDF EIRFMVDTDI VGCNWLELPA GKYALRLKEK ATQCQLEADV LWSDVVSHPP
EGPWQRIAPL RVLSFDIECA GRKGIFPEPE RDPVIQICSL GLRWGEPEPF LRLALTLRPC
APILGAKVQS YEKEEDLLQA WSTFIRIMDP DVITGYNIQN FDLPYLISRA QTLKVQTFPF
LGRVAGLCSN IRDSSFQSKQ TGRRDTKVVS MVGRVQMDML QVLLREYKLR SYTLNAVSFH
FLGEQKEDVQ HSIITDLQNG NDQTRRRLAV YCLKDAYLPL RLLERLMVLV NAVEMARVTG
VPLSYLLSRG QQVKVVSQLL RQAMHEGLLM PVVKSEGGED YTGATVIEPL KGYYDVPIAT
LDFSSLYPSI MMAHNLCYTT LLRPGTAQKL GLTEDQFIRT PTGDEFVKTS VRKGLLPQIL
ENLLSARKRA KAELAKETDP LRRQVLDGRQ LALKVSANSV YGFTGAQVGK LPCLEISQSV
TGFGRQMIEK TKQLVESKYT VENGYSTSAK VVYGDTDSVM CRFGVSSVAE AMALGREAAD
WVSGHFPSPI RLEFEKVYFP YLLISKKRYA GLLFSSRPDA HDRMDCKGLE AVRRDNCPLV
ANLVTASLRR LLIDRDPEGA VAHAQDVISD LLCNRIDISQ LVITKELTRA ASDYAGKQAH
VELAERMRKR DPGSAPSLGD RVPYVIISAA KGVAAYMKSE DPLFVLEHSL PIDTQYYLEQ
QLAKPLLRIF EPILGEGRAE AVLLRGDHTR CKTVLTGKVG GLLAFAKRRN CCIGCRTVLS
HQGAVCEFCQ PRESELYQKE VSHLNALEER FSRLWTQCQR CQGSLHEDVI CTSRDCPIFY
MRKKVRKDLE DQEQLLRRFG PPGPEAW


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