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Protein

DNA polymerase delta subunit 4

Gene

POLD4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity (PubMed:16510448, PubMed:19074196, PubMed:20334433). Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system (PubMed:24035200). Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb (PubMed:24310611). Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196). Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival (PubMed:24022480).6 Publications

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Biological processi

DNA damage, DNA excision, DNA repair, DNA replication

Enzyme and pathway databases

BioCyciZFISH:ENSG00000175482-MONOMER.
ReactomeiR-HSA-110314. Recognition of DNA damage by PCNA-containing replication complex.
R-HSA-174411. Polymerase switching on the C-strand of the telomere.
R-HSA-174414. Processive synthesis on the C-strand of the telomere.
R-HSA-174417. Telomere C-strand (Lagging Strand) Synthesis.
R-HSA-174437. Removal of the Flap Intermediate from the C-strand.
R-HSA-5358565. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
R-HSA-5358606. Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).
R-HSA-5651801. PCNA-Dependent Long Patch Base Excision Repair.
R-HSA-5656169. Termination of translesion DNA synthesis.
R-HSA-5685942. HDR through Homologous Recombination (HRR).
R-HSA-5696397. Gap-filling DNA repair synthesis and ligation in GG-NER.
R-HSA-5696400. Dual Incision in GG-NER.
R-HSA-6782135. Dual incision in TC-NER.
R-HSA-6782210. Gap-filling DNA repair synthesis and ligation in TC-NER.
R-HSA-69091. Polymerase switching.
R-HSA-69166. Removal of the Flap Intermediate.
R-HSA-69183. Processive synthesis on the lagging strand.

Names & Taxonomyi

Protein namesi
Recommended name:
DNA polymerase delta subunit 4
Alternative name(s):
DNA polymerase delta subunit p12
Gene namesi
Name:POLD4
Synonyms:POLDS
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:14106. POLD4.

Subcellular locationi

GO - Cellular componenti

  • delta DNA polymerase complex Source: GO_Central
  • nucleoplasm Source: Reactome
  • nucleus Source: ProtInc
Complete GO annotation...

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi1 – 16Missing : Complete loss of PCNA binding and of degradation after UV irradiation. 1 PublicationAdd BLAST16
Mutagenesisi4K → A: No effect on PCNA binding. 1 Publication1
Mutagenesisi4K → Q: No effect on PCNA binding, nor on degradation after UV irradiation; when associated with Y-10. No effect on PCNA binding, but normal degradation after UV irradiation; when associated with Y-10 and A-15. 1 Publication1
Mutagenesisi4K → R: No effect on ubiquitination. Loss of ubiquitination, when associated with R-15, R-25, R-74 and R-89. 1 Publication1
Mutagenesisi7I → A: Complete loss of PCNA binding; when associated with 10-AA-11. 1 Publication1
Mutagenesisi8T → A: Strongly increased stability following UV irradiation; when associated with A-9. 1 Publication1
Mutagenesisi8T → D: Complete loss of PCNA binding. 1 Publication1
Mutagenesisi9D → A: Strongly increased stability following UV irradiation; when associated with A-8. 1 Publication1
Mutagenesisi10 – 11SY → AA: Complete loss of PCNA binding; when associated with A-7. 1 Publication2
Mutagenesisi10S → Y: No effect on PCNA binding, nor on degradation after UV irradiation; when associated with Q-4. No effect on PCNA binding, but normal degradation after UV irradiation with Q-4 and A-15. 1 Publication1
Mutagenesisi15K → A: Decreased PCNA binding. No effect on PCNA binding, but normal degradation after UV irradiation; when associated with Q-4 and Y-10. Increased stability following UV irradiation and no trough during S phase; when associated with A-16 and A-17. 2 Publications1
Mutagenesisi15K → R: No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-25, R-74 and R-89. 1 Publication1
Mutagenesisi16R → A: Increased stability following UV irradiation and no trough during S phase; when associated with A-15 and A-17. 1 Publication1
Mutagenesisi17R → A: Increased stability following UV irradiation and no trough during S phase; when associated with A-15 and A-16. 1 Publication1
Mutagenesisi25K → R: No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-15, R-74 and R-89. 1 Publication1
Mutagenesisi74K → R: No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-15, R-25 and R-89. 1 Publication1
Mutagenesisi89K → R: No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-15, R-25 and R-74. 1 Publication1

Organism-specific databases

DisGeNETi57804.
OpenTargetsiENSG00000175482.
PharmGKBiPA33498.

Polymorphism and mutation databases

BioMutaiPOLD4.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001860511 – 107DNA polymerase delta subunit 4Add BLAST107

Post-translational modificationi

Ubiquitinated; undergoes 'Lys-48'-linked ubiquitination in response to UV irradiation, leading to proteasomal degradation (PubMed:17317665, PubMed:16934752, PubMed:23233665, PubMed:23913683). This modification is partly mediated by RNF8 and by the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)) (PubMed:23233665, PubMed:24022480). Efficient degradation requires the presence of PCNA and is required for the inhibition of fork progression after DNA damage (PubMed:24022480).5 Publications

Keywords - PTMi

Ubl conjugation

Proteomic databases

EPDiQ9HCU8.
MaxQBiQ9HCU8.
PaxDbiQ9HCU8.
PeptideAtlasiQ9HCU8.
PRIDEiQ9HCU8.

PTM databases

iPTMnetiQ9HCU8.
PhosphoSitePlusiQ9HCU8.

Expressioni

Developmental stagei

Expression is cell cycle-dependent, with highest levels in G2/M phase and a drastic drop in S phase (PubMed:22801543, PubMed:23913683). This trough may be mediated by DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2))-mediated proteasomal degradation (PubMed:23913683).2 Publications

Inductioni

In response to DNA damage, genotoxic stress and replication stress, following UV irradiation, ionizing radiation, treatment with methyl methanesulfonate, hydroxyurea, or with aphidicolin, protein expression drops to undetectable levels, due to proteasomal degradation (PubMed:17317665, PubMed:22801543, PubMed:23233665, PubMed:23913683, PubMed:24300032). This down-regulation is ATR-dependent (PubMed:17317665).5 Publications

Gene expression databases

BgeeiENSG00000175482.
CleanExiHS_POLD4.
ExpressionAtlasiQ9HCU8. baseline and differential.
GenevisibleiQ9HCU8. HS.

Interactioni

Subunit structurei

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 DNA polymerase and 3' to 5' proofreading exonuclease activities (PubMed:16510448, PubMed:17317665, PubMed:22801543). Within this complex, directly interacts with POLD1 and POLD2 (PubMed:12403614, PubMed:16510448). Directly interacts with PCNA, as do POLD1 and POLD3; this interaction stimulates Pol-delta4 polymerase activity (PubMed:24022480). As POLD1 and POLD2, 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). Upon genotoxic stress induced by DNA damaging agents or by replication stress, POLD4 is proteolytically degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3) which has a increased proofreading activity (PubMed:22801543, PubMed:17317665). The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2 (PubMed:12522211).7 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
PCNAP120044EBI-864968,EBI-358311
POLD1P2834011EBI-864968,EBI-716569
POLD2P490053EBI-864968,EBI-372354
WRNIP1Q96S552EBI-864968,EBI-2513471

Protein-protein interaction databases

BioGridi121774. 7 interactors.
IntActiQ9HCU8. 7 interactors.
STRINGi9606.ENSP00000311368.

Structurei

3D structure databases

ProteinModelPortaliQ9HCU8.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi1 – 16PCNA-interaction protein motif (PIP box)2 PublicationsAdd BLAST16

Sequence similaritiesi

Phylogenomic databases

eggNOGiENOG410J65P. Eukaryota.
ENOG410XUCX. LUCA.
GeneTreeiENSGT00390000005096.
HOGENOMiHOG000031022.
HOVERGENiHBG057838.
InParanoidiQ9HCU8.
KOiK03505.
OMAiEGPAGHC.
OrthoDBiEOG091G10DR.
PhylomeDBiQ9HCU8.
TreeFamiTF103004.

Family and domain databases

InterProiIPR007218. DNA_pol_delta_4.
[Graphical view]
PfamiPF04081. DNA_pol_delta_4. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9HCU8-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGRKRLITDS YPVVKRREGP AGHSKGELAP ELGEEPQPRD EEEAELELLR
60 70 80 90 100
QFDLAWQYGP CTGITRLQRW CRAKQMGLEP PPEVWQVLKT HPGDPRFQCS

LWHLYPL
Length:107
Mass (Da):12,433
Last modified:March 1, 2001 - v1
Checksum:i6F412738E4D9A19C
GO
Isoform 2 (identifier: Q9HCU8-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     63-107: GITRLQRWCRAKQMGLEPPPEVWQVLKTHPGDPRFQCSLWHLYPL → VSGISIPYEAPRKTSCP

Note: No experimental confirmation available.
Show »
Length:79
Mass (Da):8,868
Checksum:iC8CD845791BE8759
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02226939R → P.1 PublicationCorresponds to variant rs28364240dbSNPEnsembl.1
Natural variantiVAR_05752659G → R.Corresponds to variant rs34136263dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_04686463 – 107GITRL…HLYPL → VSGISIPYEAPRKTSCP in isoform 2. 1 PublicationAdd BLAST45

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF179890 mRNA. Translation: AAG08966.1.
AY928482 Genomic DNA. Translation: AAX09676.1.
AP003419 Genomic DNA. No translation available.
BG403692 mRNA. No translation available.
CCDSiCCDS58149.1. [Q9HCU8-2]
CCDS8158.1. [Q9HCU8-1]
RefSeqiNP_001243799.1. NM_001256870.1. [Q9HCU8-2]
NP_066996.3. NM_021173.4. [Q9HCU8-1]
UniGeneiHs.523829.

Genome annotation databases

EnsembliENST00000312419; ENSP00000311368; ENSG00000175482. [Q9HCU8-1]
ENST00000539074; ENSP00000444780; ENSG00000175482. [Q9HCU8-2]
GeneIDi57804.
KEGGihsa:57804.
UCSCiuc001okm.5. human. [Q9HCU8-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF179890 mRNA. Translation: AAG08966.1.
AY928482 Genomic DNA. Translation: AAX09676.1.
AP003419 Genomic DNA. No translation available.
BG403692 mRNA. No translation available.
CCDSiCCDS58149.1. [Q9HCU8-2]
CCDS8158.1. [Q9HCU8-1]
RefSeqiNP_001243799.1. NM_001256870.1. [Q9HCU8-2]
NP_066996.3. NM_021173.4. [Q9HCU8-1]
UniGeneiHs.523829.

3D structure databases

ProteinModelPortaliQ9HCU8.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121774. 7 interactors.
IntActiQ9HCU8. 7 interactors.
STRINGi9606.ENSP00000311368.

PTM databases

iPTMnetiQ9HCU8.
PhosphoSitePlusiQ9HCU8.

Polymorphism and mutation databases

BioMutaiPOLD4.

Proteomic databases

EPDiQ9HCU8.
MaxQBiQ9HCU8.
PaxDbiQ9HCU8.
PeptideAtlasiQ9HCU8.
PRIDEiQ9HCU8.

Protocols and materials databases

DNASUi57804.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000312419; ENSP00000311368; ENSG00000175482. [Q9HCU8-1]
ENST00000539074; ENSP00000444780; ENSG00000175482. [Q9HCU8-2]
GeneIDi57804.
KEGGihsa:57804.
UCSCiuc001okm.5. human. [Q9HCU8-1]

Organism-specific databases

CTDi57804.
DisGeNETi57804.
GeneCardsiPOLD4.
HGNCiHGNC:14106. POLD4.
MIMi611525. gene.
neXtProtiNX_Q9HCU8.
OpenTargetsiENSG00000175482.
PharmGKBiPA33498.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410J65P. Eukaryota.
ENOG410XUCX. LUCA.
GeneTreeiENSGT00390000005096.
HOGENOMiHOG000031022.
HOVERGENiHBG057838.
InParanoidiQ9HCU8.
KOiK03505.
OMAiEGPAGHC.
OrthoDBiEOG091G10DR.
PhylomeDBiQ9HCU8.
TreeFamiTF103004.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000175482-MONOMER.
ReactomeiR-HSA-110314. Recognition of DNA damage by PCNA-containing replication complex.
R-HSA-174411. Polymerase switching on the C-strand of the telomere.
R-HSA-174414. Processive synthesis on the C-strand of the telomere.
R-HSA-174417. Telomere C-strand (Lagging Strand) Synthesis.
R-HSA-174437. Removal of the Flap Intermediate from the C-strand.
R-HSA-5358565. Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha).
R-HSA-5358606. Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta).
R-HSA-5651801. PCNA-Dependent Long Patch Base Excision Repair.
R-HSA-5656169. Termination of translesion DNA synthesis.
R-HSA-5685942. HDR through Homologous Recombination (HRR).
R-HSA-5696397. Gap-filling DNA repair synthesis and ligation in GG-NER.
R-HSA-5696400. Dual Incision in GG-NER.
R-HSA-6782135. Dual incision in TC-NER.
R-HSA-6782210. Gap-filling DNA repair synthesis and ligation in TC-NER.
R-HSA-69091. Polymerase switching.
R-HSA-69166. Removal of the Flap Intermediate.
R-HSA-69183. Processive synthesis on the lagging strand.

Miscellaneous databases

GeneWikiiPOLD4.
GenomeRNAii57804.
PROiQ9HCU8.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000175482.
CleanExiHS_POLD4.
ExpressionAtlasiQ9HCU8. baseline and differential.
GenevisibleiQ9HCU8. HS.

Family and domain databases

InterProiIPR007218. DNA_pol_delta_4.
[Graphical view]
PfamiPF04081. DNA_pol_delta_4. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiDPOD4_HUMAN
AccessioniPrimary (citable) accession number: Q9HCU8
Secondary accession number(s): F5H506
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 26, 2001
Last sequence update: March 1, 2001
Last modified: November 30, 2016
This is version 129 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.