Affinage

POLD2

DNA polymerase delta subunit 2 · UniProt P49005

Length
469 aa
Mass
51.3 kDa
Annotated
2026-06-10
11 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POLD2 encodes the conserved small (50 kDa, B) subunit of the heterodimeric core DNA polymerase delta enzyme, where it directly binds the 125 kDa catalytic subunit to form the functional polymerase core (PMID:8530069, PMID:9286699). Beyond its structural role in the core complex, POLD2 acts as a docking platform that recruits the translesion synthesis polymerase Polη: Polη's FF483-484 (F1) motif binds POLD2 directly, and disrupting this interaction impairs bypass of bulky DNA adducts and UV-induced TT-CPD lesions, slows post-UV DNA synthesis, and reduces survival of XPV cells after UV irradiation, linking POLD2 to replication-coupled DNA damage tolerance (PMID:25662213). POLD2 is transcriptionally controlled by E2F1, which binds its promoter and drives proliferation through POLD2 in triple-negative breast cancer cells (PMID:36119494). Consistent with an essential replicative function, Pold2 is required for cellular proliferation and early mammalian development, with knockout embryos arresting at gastrulation (PMID:36528861), and its loss impairs tumor cell proliferation and sensitizes glioblastoma cells to chemo- and radiotherapy (PMID:31954770). Conserved sequence regions harboring essential-function residues have been mapped across eukaryotic orthologs (PMID:10196469).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1995 Medium

    Established the molecular identity of POLD2 as the small subunit of the core Pol δ enzyme, defining the gene product whose function would later be dissected.

    Evidence cDNA cloning and sequencing of bovine and human POLD2 with chromosomal mapping via human-hamster hybrid panels

    PMID:8530069

    Open questions at the time
    • Function inferred from conservation rather than direct biochemical assay
    • Role within the holoenzyme not yet defined
  2. 1997 Medium

    Demonstrated that the 50 kDa subunit directly contacts the 125 kDa catalytic subunit, establishing the physical architecture of the Pol δ core heterodimer.

    Evidence Yeast two-hybrid with interspecies mouse/human subunit pairs

    PMID:9286699

    Open questions at the time
    • Interaction interface not mapped
    • Single method without structural confirmation
    • Functional consequence of the interaction not tested
  3. 1999 Low

    Identified conserved sequence regions and invariant residues across eukaryotic orthologs, implicating specific regions in essential function via yeast mutant mapping.

    Evidence Comparative sequence analysis across ten species with mapping of known yeast mutant alleles

    PMID:10196469

    Open questions at the time
    • Purely computational with indirect mutant support
    • No direct functional assay of the conserved regions in human protein
  4. 2012 Medium

    Identified PIAS2 as a POLD2 interaction partner, raising the possibility of regulatory or SUMO-pathway connections.

    Evidence Yeast two-hybrid screen, direct two-hybrid, Co-IP in HEK-293, and co-localization

    PMID:22824807

    Open questions at the time
    • Functional consequence of interaction not established
    • Biological context unknown
  5. 2015 High

    Revealed a non-replicative role for POLD2 as a recruitment platform for translesion polymerase Polη, connecting the Pol δ subunit to DNA damage bypass.

    Evidence In vitro binding, in vivo Co-IP, FF483-484 motif mutagenesis, and functional rescue/survival assays in XPV cells

    PMID:25662213

    Open questions at the time
    • Structural basis of the POLD2-Polη interface not resolved
    • Whether other TLS polymerases use the same docking site unknown
  6. 2020 Medium

    Showed POLD2 drives tumor cell proliferation, invasion, and therapy resistance, positioning it as a determinant of DNA damage response in cancer.

    Evidence Knockdown/overexpression with proliferation, cycle, invasion assays and orthotopic glioblastoma xenografts with radiation

    PMID:31954770

    Open questions at the time
    • Molecular link to EGFR signaling not mechanistically defined
    • Whether effects depend on Pol δ core function or TLS role unclear
  7. 2022 High

    Established POLD2 as essential for cellular proliferation and early mammalian embryogenesis, confirming its non-redundant developmental requirement.

    Evidence Mouse knockout with blastocyst staging and outgrowth assays, recapitulated by siRNA knockdown

    PMID:36528861

    Open questions at the time
    • Cause of gastrulation failure at molecular level not defined
    • Tissue-specific requirements not dissected
  8. 2022 Medium

    Placed POLD2 downstream of E2F1 transcriptional control, linking cell-cycle transcription factors to POLD2-dependent proliferation in cancer.

    Evidence Promoter binding assay, siRNA knockdown, and rescue/overexpression in TNBC cells

    PMID:36119494

    Open questions at the time
    • Direct ChIP-defined binding site not detailed
    • Generality beyond TNBC unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How POLD2's roles in the Pol δ core versus TLS polymerase recruitment are coordinated, and the structural and regulatory basis of its partner interactions, remain unresolved.
  • No structural model of the POLD2-containing core or its damage-bypass docking complex
  • Functional role of the PIAS2 interaction unestablished
  • Mechanistic basis of cancer therapy resistance undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-69306 DNA Replication 2 R-HSA-73894 DNA Repair 1
Partners
E2F1PIAS2POLD1POLH
Complex memberships
DNA polymerase delta core complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 POLD2 encodes the small (50 kDa) subunit of the heterodimeric core DNA polymerase delta enzyme; cDNA cloning and sequencing of bovine and human POLD2 established it as a component of the Pol δ core and localized the human gene to chromosome 7. cDNA cloning, sequencing, PCR analysis of human-hamster hybrid cell lines Genomics Medium 8530069
1997 The mouse POLD2 (50 kDa) subunit directly interacts with the 125 kDa catalytic subunit of DNA polymerase delta; yeast two-hybrid showed that the mouse catalytic subunit interacts with the human 50 kDa subunit, demonstrating interspecies interaction. Yeast two-hybrid system Genomics Medium 9286699
1999 Alignment of PolD2 sequences across ten eukaryotic species (including Xenopus XlCdc1) identified ten conserved regions (I–X) containing 36 invariant amino acid positions; known yeast mutant PolD2 alleles map within conserved regions III, VI, VII, and VIII, implicating these regions in essential function. Comparative sequence analysis; cDNA cloning; mapping of existing yeast mutants to conserved regions Gene Low 10196469
2015 The FF483-484 motif (F1 motif) of human DNA polymerase eta (Polη) mediates direct interaction with POLD2 (B subunit of Pol δ) both in vitro and in vivo; mutation of this motif impairs Polη-dependent bypass of an N-2-acetylaminofluorene adduct and a TT-CPD lesion in cellular extracts, reduces DNA synthesis progression after UV, and decreases cell survival after UV irradiation in XPV cells. In vitro binding assay, co-immunoprecipitation (in vivo), complementation of XPV cells with Polη mutants, cell survival assay, DNA synthesis assay in cellular extracts Nucleic acids research High 25662213
2012 POLD2 interacts with PIAS2 (protein inhibitor of activated STAT2); the interaction was identified by yeast two-hybrid screening, confirmed by direct yeast two-hybrid, validated by co-immunoprecipitation in HEK-293 cells, and the two proteins were shown to partially co-localize in mammalian cells. Yeast two-hybrid screening, direct yeast two-hybrid, co-immunoprecipitation, subcellular co-localization International journal of molecular medicine Medium 22824807
2022 POLD2 is essential for early murine embryogenesis; Pold2 knockout embryos develop normally to E3.5 blastocyst stage but fail at gastrulation, cannot hatch from zona pellucida, show slowed cellular proliferation, and exhibit skewed primitive endoderm and epiblast allocation; siRNA knockdown recapitulated these phenotypes. Genetic knockout in mouse, siRNA knockdown, outgrowth assay, blastocyst staging Molecular reproduction and development High 36528861
2022 Transcription factor E2F1 directly binds the promoter of POLD2 and regulates its expression in triple-negative breast cancer (TNBC) cells; E2F1-mediated cell proliferation in TNBC is dependent on POLD2, as rescue experiments showed that POLD2 re-expression restores proliferation upon E2F1-driven induction. Promoter binding assay (ChIP or reporter), siRNA knockdown, rescue/overexpression experiments Frontiers in oncology Medium 36119494
2020 POLD2 knockdown inhibits GBM cell proliferation, cell cycle progression, and invasiveness, sensitizes GBM cells to chemo/radiation-induced cell death, and reverses the cytoprotective effects of EGFR signaling; forced POLD2 expression induces GBM cell proliferation, colony formation, invasiveness, and chemo/radiation resistance; shRNA-POLD2 combined with radiation dramatically inhibited orthotopic xenograft growth in vivo. siRNA/shRNA knockdown, forced overexpression, cell proliferation/cycle/invasion assays, orthotopic xenograft mouse model, radiation treatment Cancer letters Medium 31954770

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 POLD2 and KSP37 (FGFBP2) correlate strongly with histology, stage and outcome in ovarian carcinomas. PloS one 31 21079801
1995 Cloning of the cDNAs for the small subunits of bovine and human DNA polymerase delta and chromosomal location of the human gene (POLD2). Genomics 31 8530069
2015 FF483-484 motif of human Polη mediates its interaction with the POLD2 subunit of Polδ and contributes to DNA damage tolerance. Nucleic acids research 26 25662213
2012 Characterization of Mycobacterium smegmatis PolD2 and PolD1 as RNA/DNA polymerases homologous to the POL domain of bacterial DNA ligase D. Biochemistry 20 23198659
2022 POLD2 is activated by E2F1 to promote triple-negative breast cancer proliferation. Frontiers in oncology 12 36119494
2020 ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics. Cancer letters 12 31954770
1999 Characterisation of XlCdc1, a Xenopus homologue of the small (PolD2) subunit of DNA polymerase delta; identification of ten conserved regions I-X based on protein sequence comparisons across ten eukaryotic species. Gene 11 10196469
2021 Exome sequencing reveals novel rare variants in Iranian familial multiple sclerosis: The importance of POLD2 in the disease pathogenesis. Genomics 10 34116171
1997 Cloning, chromosomal localization, and interspecies interaction of mouse DNA polymerase delta small subunit (PolD2). Genomics 6 9286699
2022 Early embryonic lethality of mice lacking POLD2. Molecular reproduction and development 5 36528861
2012 Identification of Pold2 as a novel interaction partner of protein inhibitor of activated STAT2. International journal of molecular medicine 3 22824807

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