DNA polymerase delta catalytic subunit

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. 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. 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. Along with DNA polymerase kappa, DNA polymerase delta carries out approximately half of nucleotide excision repair (NER) synthesis following UV irradiation. 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). Involved in the translesion synthesis (TLS) of templates carrying O6-methylguanine, 8oxoG or abasic sites.

Classification

Family (Pfam)

PF00136 DNA_pol_B, PF03104 DNA_pol_B_exo1, PF24055 POL3_N, PF14260 zf-C4pol

InterPro

DNA-dir_DNA_pol_B, DNA-dir_DNA_pol_B_CS, DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA/RNA_pol_sf, DNA_pol_B_thumb, DNA_pol_palm_dom_sf, DNA_pol_type-B, DPOD/Z_N, RNaseH-like_sf, RNaseH_sf, Znf-C4pol

Functional cluster

Eukaryotic Transcription Factors & related

Experimental structures · PDB · 6

• 6S1M EM 4.27A
• 6S1N EM 4.86A
• 6S1O EM 8.10A
• 6TNY EM 3.08A
• 6TNZ EM 4.05A
• 9EKB EM 3.65A

A predicted model is available from AlphaFold.

Gene Ontology · 25

• GO:0043625 delta DNA polymerase complex
• GO:0016020 membrane
• GO:0005654 nucleoplasm
• GO:0000109 nucleotide-excision repair complex
• GO:0005634 nucleus
• GO:0008296 3'-5'-DNA exonuclease activity
• GO:0051539 4 iron, 4 sulfur cluster binding
• GO:0003682 chromatin binding
• GO:0003684 damaged DNA binding
• GO:0003677 DNA binding
• GO:0003887 DNA-directed DNA polymerase activity
• GO:0019899 enzyme binding
• GO:0000166 nucleotide binding
• GO:0008270 zinc ion binding
• GO:0006287 base-excision repair, gap-filling
• GO:0071897 DNA biosynthetic process
• GO:0006281 DNA repair
• GO:0006260 DNA replication
• GO:0045004 DNA replication proofreading
• GO:0000731 DNA synthesis involved in DNA repair
• GO:0006261 DNA-templated DNA replication
• GO:0070987 error-free translesion synthesis
• GO:0055089 fatty acid homeostasis
• GO:0006297 nucleotide-excision repair, DNA gap filling
• GO:0009411 response to UV

Disease associations

• colorectal cancer, susceptibility to, 10 MONDO:0012953
• mandibular hypoplasia-deafness-progeroid syndrome MONDO:0014157
• immunodeficiency 120 MONDO:0970994

Drugs targeting this protein · 6

• FLUDARABINE PHOSPHATE inhibitor
• GEMCITABINE HYDROCHLORIDE inhibitor
• CLOFARABINE inhibitor
• TROXACITABINE inhibitor
• ASPACYTARABINE inhibitor
• CYTARABINE inhibitor

Related proteins · sequence + function similarity

• DNA polymerase delta catalytic subunit 0.99
• DNA polymerase delta catalytic subunit 0.98
• DNA polymerase delta catalytic subunit 0.98
• DNA polymerase delta catalytic subunit 0.96
• DNA polymerase delta catalytic subunit 0.84
• DNA polymerase catalytic subunit 0.83
• DNA polymerase catalytic subunit 0.83
• DNA polymerase catalytic subunit 0.83
• DNA polymerase delta catalytic subunit 0.81
• DNA polymerase delta catalytic subunit 0.80
• DNA polymerase delta catalytic subunit 0.79
• DNA polymerase catalytic subunit 0.78

Co-cited proteins · studied together in the literature

• DNA polymerase delta subunit 2 14 shared papers
• DNA polymerase delta subunit 4 12 shared papers
• DNA polymerase delta subunit 3 13 shared papers
• DNA polymerase epsilon catalytic subunit A 3 shared papers
• Polymerase delta-interacting protein 2 2 shared papers
• ATPase WRNIP1 1 shared papers
• DNA sliding clamp PCNA 5 shared papers
• Cytosolic iron-sulfur assembly component 2A 2 shared papers
• Cytosolic iron-sulfur assembly component 2A 2 shared papers
• Serine/threonine-protein kinase B-raf 1 shared papers
• Iron-responsive element-binding protein 2 1 shared papers
• Probable cytosolic iron-sulfur protein assembly protein CIAO1 1 shared papers

Literature · 31 cited papers

• Combined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1. J. Allergy Clin. Immunol. · 2020
• Polymerase delta deficiency causes syndromic immunodeficiency with replicative stress. J. Clin. Invest. · 2019
• Human CIA2A-FAM96A and CIA2B-FAM96B Integrate Iron Homeostasis and Maturation of Different Subsets of Cytosolic-Nuclear Iron-Sulfur Proteins. Cell Metab. · 2018
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• CBP and p300 acetylate PCNA to link its degradation with nucleotide excision repair synthesis. Nucleic Acids Res. · 2014
• New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum. Mol. Genet. · 2014
• Break-induced replication repair of damaged forks induces genomic duplications in human cells. Science · 2014
• DNA polymerase delta-interacting protein 2 is a processivity factor for DNA polymerase lambda during 8-oxo-7,8-dihydroguanine bypass. Proc. Natl. Acad. Sci. U.S.A. · 2013
• Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics · 2014
• Dynamics of enzymatic interactions during short flap human Okazaki fragment processing by two forms of human DNA polymerase delta. DNA Repair · 2013
• Degradation of p12 subunit by CRL4Cdt2 E3 ligase inhibits fork progression after DNA damage. J. Biol. Chem. · 2013
• 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. · 2013
• … and 19 more in the literature graph