DPOD3_MOUSE
ID DPOD3_MOUSE Reviewed; 462 AA.
AC Q9EQ28;
DT 26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2001, sequence version 2.
DT 03-AUG-2022, entry version 132.
DE RecName: Full=DNA polymerase delta subunit 3;
DE AltName: Full=DNA polymerase delta subunit p66;
GN Name=Pold3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=BALB/cJ; TISSUE=Testis;
RA Anway M.D., Li Y., Griswold M.D.;
RT "Identification of testicular germ cell gene expression by differential
RT display analysis.";
RL Submitted (AUG-2000) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP PARTIAL PROTEIN SEQUENCE, AND FUNCTION.
RX PubMed=10219083; DOI=10.1093/nar/27.10.2108;
RA Hughes P., Tratner I., Ducoux M., Piard K., Baldacci G.;
RT "Isolation and identification of the third subunit of mammalian DNA
RT polymerase delta by PCNA-affinity chromatography of mouse FM3A cell
RT extracts.";
RL Nucleic Acids Res. 27:2108-2114(1999).
RN [3]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-306, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [4]
RP FUNCTION IN POL-DELTA COMPLEX STABILIZATION, DISRUPTION PHENOTYPE,
RP SUBCELLULAR LOCATION, AND INTERACTION WITH POLD1; POLD2 AND POLD4.
RX PubMed=27524497; DOI=10.1016/j.molcel.2016.07.007;
RA Murga M., Lecona E., Kamileri I., Diaz M., Lugli N., Sotiriou S.K.,
RA Anton M.E., Mendez J., Halazonetis T.D., Fernandez-Capetillo O.;
RT "POLD3 Is Haploinsufficient for DNA Replication in Mice.";
RL Mol. Cell 63:877-883(2016).
CC -!- FUNCTION: Accessory component of both the DNA polymerase delta complex
CC and the DNA polymerase zeta complex (By similarity). As a component of
CC the trimeric and tetrameric DNA polymerase delta complexes (Pol-delta3
CC and Pol-delta4, respectively), plays a role in high fidelity genome
CC replication, including in lagging strand synthesis, and repair
CC (PubMed:10219083, PubMed:27524497). Required for optimal Pol-delta
CC activity. Stabilizes the Pol-delta complex and plays a major role in
CC Pol-delta stimulation by PCNA. Pol-delta3 and Pol-delta4 are
CC characterized by the absence or the presence of POLD4. They exhibit
CC differences in catalytic activity. Most notably, Pol-delta3 shows
CC higher proofreading activity than Pol-delta4. Although both Pol-delta3
CC and Pol-delta4 process Okazaki fragments in vitro, Pol-delta3 may also
CC be better suited to fulfill this task, exhibiting near-absence of
CC strand displacement activity compared to Pol-delta4 and stalling on
CC encounter with the 5'-blocking oligonucleotides. Pol-delta3 idling
CC process may avoid the formation of a gap, while maintaining a nick that
CC can be readily ligated. Along with DNA polymerase kappa, DNA polymerase
CC delta carries out approximately half of nucleotide excision repair
CC (NER) synthesis following UV irradiation. In this context, POLD3, along
CC with PCNA and RFC1-replication factor C complex, is required to recruit
CC POLD1, the catalytic subunit of the polymerase delta complex, to DNA
CC damage sites. Under conditions of DNA replication stress, required for
CC the repair of broken replication forks through break-induced
CC replication (BIR). Involved in the translesion synthesis (TLS) of
CC templates carrying O6-methylguanine or abasic sites performed by Pol-
CC delta4, independently of DNA polymerase zeta (REV3L) or eta (POLH).
CC Facilitates abasic site bypass by DNA polymerase delta by promoting
CC extension from the nucleotide inserted opposite the lesion. Also
CC involved in TLS, as a component of the tetrametric DNA polymerase zeta
CC complex. Along with POLD2, dramatically increases the efficiency and
CC processivity of DNA synthesis of the DNA polymerase zeta complex
CC compared to the minimal zeta complex, consisting of only REV3L and REV7
CC (By similarity). {ECO:0000250|UniProtKB:Q15054,
CC ECO:0000269|PubMed:10219083, ECO:0000269|PubMed:27524497}.
CC -!- SUBUNIT: Component of both the DNA polymerase delta and DNA polymerase
CC zeta complexes (By similarity). The tetrameric DNA polymerase delta
CC complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50,
CC POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3'
CC to 5' proofreading exonuclease activities (PubMed:27524497). Within
CC this complex, directly interacts with POLD2. Following stress caused by
CC DNA damaging agents or by replication stress, POLD4 is degraded and
CC Pol-delta4 is converted into a trimeric form of the complex (Pol-
CC delta3), which consists of POLD1, POLD2 and POLD3. Pol-delta3 is the
CC major form occurring at S phase replication sites, as well as DNA
CC damage sites. Directly interacts with PCNA, as do POLD1 and POLD4; this
CC interaction stimulates Pol-delta polymerase activity. POLD3
CC phosphorylation at Ser-454 impairs PCNA binding. Component of the DNA
CC polymerase zeta complex (POLZ), which consists of REV3L, MAD2L2, POLD2
CC and POLD3, with REV3L bearing DNA polymerase catalytic activity. The
CC DNA polymerase delta complex interacts with POLDIP2; this interaction
CC is probably mediated through direct binding to POLD2 (By similarity).
CC {ECO:0000250|UniProtKB:Q15054, ECO:0000269|PubMed:27524497}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27524497}. Nucleus
CC {ECO:0000269|PubMed:27524497}. Note=Partially colocalizes with PCNA and
CC POLD1 at S phase replication sites. Recruited to DNA damage sites
CC within 2 hours following UV irradiation.
CC {ECO:0000250|UniProtKB:Q15054}.
CC -!- DOMAIN: The PIP-box mediates the interaction with PCNA.
CC {ECO:0000250|UniProtKB:Q15054}.
CC -!- PTM: Ubiquitinated, but not targeted to the proteasome. Sumoylated.
CC Sumoylation by SUMO3 may be predominant.
CC {ECO:0000250|UniProtKB:Q15054}.
CC -!- PTM: Phosphorylation at Ser-454 is thought to decrease the affinity for
CC PCNA and Pol-delta4 processivity. May be phosphorylated by CDK1-cyclin-
CC A complex, as well as CDK2-cyclin-A and CDK2-cyclin-E complexes. PCNA
CC interferes with CDK-cyclin phosphorylation.
CC {ECO:0000250|UniProtKB:Q15054}.
CC -!- DISRUPTION PHENOTYPE: In a conditional knockdown, embryonic lethal when
CC homozygous. Induction of the knockdown in adult animals results in a
CC generalized accumulation of DNA damage and ultimately death of all mice
CC within 15 weeks after the beginning of the treatment. Heterozygous
CC animals are born at sub-Mendelian ratios, and, of those born, some are
CC dwarfs, present hydrocephaly and have a reduced lifespan. In cells,
CC Pold3 deficiency leads to replication stress and cell death.
CC {ECO:0000269|PubMed:27524497}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAG45967.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF294329; AAG45967.1; ALT_INIT; mRNA.
DR RefSeq; XP_006508212.2; XM_006508149.2.
DR AlphaFoldDB; Q9EQ28; -.
DR SMR; Q9EQ28; -.
DR ComplexPortal; CPX-2098; DNA polymerase delta complex.
DR CORUM; Q9EQ28; -.
DR IntAct; Q9EQ28; 1.
DR STRING; 10090.ENSMUSP00000032969; -.
DR iPTMnet; Q9EQ28; -.
DR PhosphoSitePlus; Q9EQ28; -.
DR EPD; Q9EQ28; -.
DR jPOST; Q9EQ28; -.
DR MaxQB; Q9EQ28; -.
DR PaxDb; Q9EQ28; -.
DR PRIDE; Q9EQ28; -.
DR ProteomicsDB; 279478; -.
DR UCSC; uc009imk.1; mouse.
DR MGI; MGI:1915217; Pold3.
DR eggNOG; ENOG502QPSW; Eukaryota.
DR InParanoid; Q9EQ28; -.
DR OrthoDB; 1550733at2759; -.
DR PhylomeDB; Q9EQ28; -.
DR Reactome; R-MMU-110314; Recognition of DNA damage by PCNA-containing replication complex.
DR Reactome; R-MMU-174411; Polymerase switching on the C-strand of the telomere.
DR Reactome; R-MMU-174414; Processive synthesis on the C-strand of the telomere.
DR Reactome; R-MMU-174417; Telomere C-strand (Lagging Strand) Synthesis.
DR Reactome; R-MMU-174437; Removal of the Flap Intermediate from the C-strand.
DR Reactome; R-MMU-5358565; Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
DR Reactome; R-MMU-5358606; Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).
DR Reactome; R-MMU-5651801; PCNA-Dependent Long Patch Base Excision Repair.
DR Reactome; R-MMU-5656169; Termination of translesion DNA synthesis.
DR Reactome; R-MMU-5685942; HDR through Homologous Recombination (HRR).
DR Reactome; R-MMU-5696397; Gap-filling DNA repair synthesis and ligation in GG-NER.
DR Reactome; R-MMU-5696400; Dual Incision in GG-NER.
DR Reactome; R-MMU-6782135; Dual incision in TC-NER.
DR Reactome; R-MMU-6782210; Gap-filling DNA repair synthesis and ligation in TC-NER.
DR Reactome; R-MMU-69091; Polymerase switching.
DR Reactome; R-MMU-69166; Removal of the Flap Intermediate.
DR Reactome; R-MMU-69183; Processive synthesis on the lagging strand.
DR BioGRID-ORCS; 67967; 28 hits in 106 CRISPR screens.
DR ChiTaRS; Pold3; mouse.
DR PRO; PR:Q9EQ28; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9EQ28; protein.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0043625; C:delta DNA polymerase complex; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0016035; C:zeta DNA polymerase complex; ISO:MGI.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:MGI.
DR GO; GO:0071897; P:DNA biosynthetic process; IDA:UniProtKB.
DR GO; GO:0006271; P:DNA strand elongation involved in DNA replication; IBA:GO_Central.
DR GO; GO:1904161; P:DNA synthesis involved in UV-damage excision repair; IBA:GO_Central.
DR GO; GO:0006261; P:DNA-templated DNA replication; ISO:MGI.
DR GO; GO:0042276; P:error-prone translesion synthesis; ISO:MGI.
DR GO; GO:0006297; P:nucleotide-excision repair, DNA gap filling; ISO:MGI.
DR Gene3D; 3.90.1030.20; -; 1.
DR InterPro; IPR019038; POLD3.
DR InterPro; IPR041913; POLD3_sf.
DR PANTHER; PTHR17598; PTHR17598; 1.
DR Pfam; PF09507; CDC27; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Direct protein sequencing; DNA damage;
KW DNA excision; DNA repair; DNA replication; Isopeptide bond; Nucleus;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT CHAIN 2..462
FT /note="DNA polymerase delta subunit 3"
FT /id="PRO_0000186048"
FT REGION 144..186
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 200..230
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 254..384
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 403..462
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 452..459
FT /note="PIP-box"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT COMPBIAS 150..186
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 283..316
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 345..366
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 403..418
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 426..442
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT MOD_RES 306
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 403
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT MOD_RES 405
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT MOD_RES 407
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT MOD_RES 409
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT MOD_RES 454
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT CROSSLNK 256
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT CROSSLNK 256
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT CROSSLNK 259
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT CROSSLNK 429
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
FT CROSSLNK 429
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q15054"
SQ SEQUENCE 462 AA; 50836 MW; FF3F67E065A08B36 CRC64;
MAEQLYLENI DEFVTDQNKI VTYKWLSYTL GVHVNQAKQM LYEYVERKRK ENSGAQLHVT
YLVSGSLIQN GHSCHKVAVV REDKLEAVKS KLAVTASIHV YSIQKAMLKD SGPLFNTDYD
ILKSNLQNCS KFSAIQCAAA VPRAPAESPS SRKYEQSNLQ AASEAQASEL TTNGHGPPAS
KQASQQPKGI MGMLISKAAT KTQDTNKETK PEAREVTSAS SAGGKAPGKG SVMSNFFGKA
AMNKLKVNLD SEQAVKEEKT VEQPPVSVTE PKLAAPPAQK KSSRKSEPGK VQQKEKSSRG
KRVDLSDEEA KETEHLKKKR RRIKLPQSDS SEDEVFEDSP EMYEADSPSP PPVSPPPDPM
PKTEPPPVKR SSGETKRRRK RVLKSKTFVD EEGCIVTEKV YESESCTDSE EELKMKPASA
HKPPAAAVKR EPREERKGPK KGAAALGKAN RQVSITGFFQ KK
