Q9HCU8 · DPOD4_HUMAN
- ProteinDNA polymerase delta subunit 4
- GenePOLD4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids107 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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).
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).
GO annotations
all annotations | all molecular function | virus receptor activity | dna binding | rna binding | cytoskeletal motor activity | catalytic activity | gtpase activity | structural molecule activity | transporter activity | cytoskeletal protein binding | lipid binding | cyclase activity | antioxidant activity | oxidoreductase activity | transferase activity | hydrolase activity | lyase activity | isomerase activity | ligase activity | protein tag activity | cargo receptor activity | histone binding | protein folding chaperone | translation regulator activity | nutrient reservoir activity | receptor ligand activity | molecular transducer activity | molecular adaptor activity | toxin activity | cell adhesion mediator activity | molecular function regulator activity | virus coreceptor activity | catalytic activity, acting on a protein | catalytic activity, acting on dna | catalytic activity, acting on rna | molecular carrier activity | transcription regulator activity | general transcription initiation factor activity | molecular sensor activity | molecular sequestering activity | atp-dependent activity | other molecular function | all biological process | mitotic cell cycle | cytokinesis | cytoplasmic translation | immune system process | muscle system process | circulatory system process | renal system process | respiratory system process | carbohydrate metabolic process | generation of precursor metabolites and energy | dna replication | dna repair | dna recombination | chromatin organization | dna-templated transcription | regulation of dna-templated transcription | trna metabolic process | protein folding | protein glycosylation | amino acid metabolic process | modified amino acid metabolic process | lipid metabolic process | vitamin metabolic process | sulfur compound metabolic process | intracellular protein transport | nucleocytoplasmic transport | autophagy | inflammatory response | mitochondrion organization | cytoskeleton organization | microtubule-based movement | peroxisome organization | lysosome organization | chromosome segregation | cell adhesion | establishment or maintenance of cell polarity | programmed cell death | photosynthesis | mrna metabolic process | snrna metabolic process | vesicle-mediated transport | reproductive process | digestive system process | signaling | cell differentiation | protein catabolic process | extracellular matrix organization | regulatory ncrna-mediated gene silencing | telomere organization | cell junction organization | wound healing | ribosome biogenesis | cilium organization | anatomical structure development | cell motility | nervous system process | endocrine process | protein maturation | transmembrane transport | nucleobase-containing small molecule metabolic process | hepaticobiliary system process | membrane organization | protein-containing complex assembly | cell wall organization or biogenesis | nitrogen cycle metabolic process | protein localization to plasma membrane | defense response to other organism | detoxification | meiotic nuclear division | mitotic nuclear division | mitochondrial gene expression | carbohydrate derivative metabolic process | other biological process | all cellular component | nuclear chromosome | extracellular region | extracellular space | cell wall | nucleus | nuclear envelope | nucleoplasm | chromosome | nucleolus | mitochondrion | lysosome | endosome | vacuole | peroxisome | endoplasmic reticulum | golgi apparatus | lipid droplet | microtubule organizing center | cytosol | ribosome | cytoskeleton | plasma membrane | cilium | plastid | thylakoid | external encapsulating structure | extracellular matrix | cytoplasmic vesicle | organelle | other cellular component | |||
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Aspect | Term | |
---|---|---|
Cellular Component | delta DNA polymerase complex | |
Cellular Component | nucleoplasm | |
Biological Process | DNA synthesis involved in DNA repair | |
Biological Process | DNA-templated DNA replication | |
Biological Process | positive regulation of endothelial cell proliferation |
Keywords
- Biological process
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameDNA polymerase delta subunit 4
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9HCU8
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: Partially recruited to DNA damage sites within 2 hours following UV irradiation, before degradation.
Keywords
- Cellular component
Disease & Variants
Features
Showing features for mutagenesis, natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 1-16 | Complete loss of PCNA binding and of degradation after UV irradiation. | ||||
Sequence: Missing | ||||||
Mutagenesis | 4 | No effect on PCNA binding. | ||||
Sequence: K → A | ||||||
Mutagenesis | 4 | 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. | ||||
Sequence: K → Q | ||||||
Mutagenesis | 4 | No effect on ubiquitination. Loss of ubiquitination, when associated with R-15, R-25, R-74 and R-89. | ||||
Sequence: K → R | ||||||
Mutagenesis | 7 | Complete loss of PCNA binding; when associated with 10-AA-11. | ||||
Sequence: I → A | ||||||
Mutagenesis | 8 | Strongly increased stability following UV irradiation; when associated with A-9. | ||||
Sequence: T → A | ||||||
Mutagenesis | 8 | Complete loss of PCNA binding. | ||||
Sequence: T → D | ||||||
Mutagenesis | 9 | Strongly increased stability following UV irradiation; when associated with A-8. | ||||
Sequence: D → A | ||||||
Mutagenesis | 10 | 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. | ||||
Sequence: S → Y | ||||||
Mutagenesis | 10-11 | Complete loss of PCNA binding; when associated with A-7. | ||||
Sequence: SY → AA | ||||||
Mutagenesis | 15 | 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. | ||||
Sequence: K → A | ||||||
Mutagenesis | 15 | No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-25, R-74 and R-89. | ||||
Sequence: K → R | ||||||
Mutagenesis | 16 | Increased stability following UV irradiation and no trough during S phase; when associated with A-15 and A-17. | ||||
Sequence: R → A | ||||||
Mutagenesis | 17 | Increased stability following UV irradiation and no trough during S phase; when associated with A-15 and A-16. | ||||
Sequence: R → A | ||||||
Mutagenesis | 25 | No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-15, R-74 and R-89. | ||||
Sequence: K → R | ||||||
Natural variant | VAR_022269 | 39 | in dbSNP:rs28364240 | |||
Sequence: R → P | ||||||
Natural variant | VAR_057526 | 59 | in dbSNP:rs34136263 | |||
Sequence: G → R | ||||||
Mutagenesis | 74 | No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-15, R-25 and R-89. | ||||
Sequence: K → R | ||||||
Mutagenesis | 89 | No effect on ubiquitination. Loss of ubiquitination; when associated with R-4, R-15, R-25 and R-74. | ||||
Sequence: K → R |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 127 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000186051 | 1-107 | DNA polymerase delta subunit 4 | |||
Sequence: MGRKRLITDSYPVVKRREGPAGHSKGELAPELGEEPQPRDEEEAELELLRQFDLAWQYGPCTGITRLQRWCRAKQMGLEPPPEVWQVLKTHPGDPRFQCSLWHLYPL |
Post-translational modification
Ubiquitinated; undergoes 'Lys-48'-linked ubiquitination in response to UV irradiation, leading to proteasomal degradation (PubMed:16934752, PubMed:17317665, 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).
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).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Induction
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).
This down-regulation is ATR-dependent (PubMed:17317665).
Developmental stage
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).
This trough may be mediated by DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2))-mediated proteasomal degradation (PubMed:23913683).
Gene expression databases
Organism-specific databases
Interaction
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 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 an increased proofreading activity (PubMed:17317665, PubMed:22801543).
The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2 (PubMed:12522211).
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 an increased proofreading activity (PubMed:17317665, PubMed:22801543).
The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2 (PubMed:12522211).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9HCU8 | PCNA P12004 | 4 | EBI-864968, EBI-358311 | |
BINARY | Q9HCU8 | POLD1 P28340 | 14 | EBI-864968, EBI-716569 | |
BINARY | Q9HCU8 | POLD2 P49005 | 7 | EBI-864968, EBI-372354 | |
BINARY | Q9HCU8 | WRNIP1 Q96S55 | 2 | EBI-864968, EBI-2513471 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for motif, compositional bias, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Motif | 1-16 | PCNA-interaction protein motif (PIP box) | ||||
Sequence: MGRKRLITDSYPVVKR | ||||||
Compositional bias | 1-35 | Basic and acidic residues | ||||
Sequence: MGRKRLITDSYPVVKRREGPAGHSKGELAPELGEE | ||||||
Region | 1-44 | Disordered | ||||
Sequence: MGRKRLITDSYPVVKRREGPAGHSKGELAPELGEEPQPRDEEEA |
Sequence similarities
Belongs to the DNA polymerase delta subunit 4 family.
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q9HCU8-1
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.
- Name1
- Length107
- Mass (Da)12,433
- Last updated2001-03-01 v1
- Checksum6F412738E4D9A19C
Q9HCU8-2
- Name2
- Differences from canonical
- 63-107: GITRLQRWCRAKQMGLEPPPEVWQVLKTHPGDPRFQCSLWHLYPL → VSGISIPYEAPRKTSCP
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
E9PL15 | E9PL15_HUMAN | POLD4 | 32 |
Features
Showing features for compositional bias, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 1-35 | Basic and acidic residues | ||||
Sequence: MGRKRLITDSYPVVKRREGPAGHSKGELAPELGEE | ||||||
Alternative sequence | VSP_046864 | 63-107 | in isoform 2 | |||
Sequence: GITRLQRWCRAKQMGLEPPPEVWQVLKTHPGDPRFQCSLWHLYPL → VSGISIPYEAPRKTSCP |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF179890 EMBL· GenBank· DDBJ | AAG08966.1 EMBL· GenBank· DDBJ | mRNA | ||
AY928482 EMBL· GenBank· DDBJ | AAX09676.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AP003419 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BG403692 EMBL· GenBank· DDBJ | - | mRNA | No translation available. |