Affinage

POLD1

DNA polymerase delta catalytic subunit · UniProt P28340

Length
1107 aa
Mass
123.6 kDa
Annotated
2026-06-10
97 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POLD1 encodes the catalytic p125 subunit of DNA polymerase δ, an enzyme essential for S-phase progression and genome stability whose loss causes increased DNA breaks, chromosome abnormalities, and reduced replication origin firing (PMID:27974823, PMID:26087769). The protein carries two separable catalytic activities: a 5'-3' DNA polymerase function and a 3'-5' exonuclease proofreading function residing in a DEDD motif (D316/E318/D402/D515) that coordinates two magnesium cations for nuclease catalysis (PMID:38067377). The genetic separability of these activities underlies distinct disease mechanisms: germline exonuclease-domain mutations (e.g., p.Ser478Asn, L474P, D402N) impair mispair correction and produce a base-substitution mutator phenotype, acting recessively at the cellular level such that high tumor mutation rates and the SBS10d signature emerge only after somatic loss of the wild-type allele (PMID:23263490, PMID:38067377, PMID:38658779), whereas the in-frame p.Ser605del deletion abolishes polymerase activity while sparing proofreading and causes the MDPL multisystem progeroid disorder (mandibular hypoplasia, deafness, lipodystrophy) (PMID:23770608). Reduced polymerase activity with intact proofreading produces a milder, tissue-specific autosomal recessive sensorineural hearing loss when combined with a null allele (PMID:31944473), and the MDPL p.Ser605del variant additionally creates an aberrant FSLYP motif that drives abnormal interaction with the telomeric protein TRF1, linking it to telomere dysfunction and premature aging (PMID:41219970). POLD1 transcription is tightly cell-cycle-regulated: its TATA-less promoter is activated by Sp1/Sp3 and an E2F-like element at the G1/S boundary (PMID:9030545), modulated by a CDE/CHR element responsive to E2F1 and p21 (PMID:19557333), and repressed by p53 through competition with Sp1 at an overlapping binding site (PMID:11375983); declining E2F1 and CTCF binding with age, alongside promoter methylation, downregulates POLD1 during replicative senescence (PMID:30895337, PMID:33692996). PRMT7 acting through the BRG1/SWI-SNF complex methylates histone H2A/H4 Arg-3 at the POLD1 promoter to repress expression, and this repression controls cellular sensitivity to DNA-damaging agents (PMID:22761421). Beyond DNA synthesis, POLD1 stabilizes the MYC oncoprotein in a polymerase-independent manner by binding the MYC MB1 domain and competing with the E3 ligase FBXW7, forming a MYC–POLD1 positive feedback loop (PMID:37105989), and drives pathological cardiomyocyte endoreplication and hypertrophy via a p21–PCNA–POLD1 interaction axis (PMID:40948130). POLD1 deficiency is synthetically lethal with ATR/CHK1 inhibition (PMID:26755646, PMID:33144657).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1997 High

    Established how POLD1 transcription is wired to the cell cycle, showing the TATA-less promoter depends on Sp1/Sp3 and an E2F-like element for its G1/S induction.

    Evidence Footprinting, EMSA, luciferase reporters and Drosophila SL2 cotransfection

    PMID:9030545

    Open questions at the time
    • Did not define how the E2F-like element integrates with cell-cycle signaling
    • Endogenous chromatin context not addressed
  2. 2001 High

    Showed p53 represses POLD1 by competing with Sp1 at an overlapping promoter site, connecting POLD1 levels to tumor-suppressor surveillance and explaining derepression by tumor-derived p53 mutants.

    Evidence EMSA, regulated p53 expression system, reporter assays

    PMID:11375983

    Open questions at the time
    • Did not address physiological consequences of altered POLD1 dosage
    • Indirect methylation routes not yet integrated
  3. 2004 Medium

    Tested whether POLD1 status drives the mutator phenotype of DLD-1 cancer cells, finding MSH6 rather than POLD1 was responsible — an early epistasis result distinguishing mismatch-repair from polymerase contributions.

    Evidence Stable WT POLD1/MSH6 complementation and HPRT mutation frequency assay

    PMID:14767555

    Open questions at the time
    • Negative result for POLD1 specific to this cell line
    • Did not test exonuclease-mutant alleles directly
  4. 2009 Medium

    Identified a CDE/CHR element conferring cell-cycle-dependent repression of POLD1 by E2F1 and p21, refining the transcriptional control circuit.

    Evidence Promoter-mutation luciferase reporters and EMSA

    PMID:19557333

    Open questions at the time
    • Identities of the three binding complexes not fully resolved
    • Single lab, single promoter context
  5. 2012 High

    Defined an epigenetic repressor of POLD1, showing PRMT7 within the BRG1/SWI-SNF complex methylates histone Arg-3 at the promoter to set DNA-damage sensitivity, with POLD1 as the critical downstream effector.

    Evidence Reciprocal Co-IP, ChIP, shRNA knockdown with epistatic POLD1 re-knockdown

    PMID:22761421

    Open questions at the time
    • Signals controlling PRMT7 recruitment unknown
    • Generality across cell types untested
  6. 2012 High

    Demonstrated that germline POLD1 exonuclease-domain mutations cause a heritable base-substitution mutator phenotype, defining proofreading loss as a cancer-predisposition mechanism.

    Evidence Whole-genome sequencing, family linkage, yeast functional proofreading assays

    PMID:23263490

    Open questions at the time
    • Cellular dominance/recessivity of the defect not resolved at this stage
    • Tissue specificity of tumor risk unexplained
  7. 2013 High

    Separated polymerase from exonuclease function genetically, showing the p.Ser605del active-site deletion abolishes polymerase activity while sparing proofreading and causes the MDPL syndrome.

    Evidence Genomic sequencing and in vitro enzymatic assays distinguishing polymerase vs exonuclease activity

    PMID:23770608

    Open questions at the time
    • Did not explain how a replication defect produces a progeroid phenotype
    • Molecular partner mediating tissue effects unknown
  8. 2015 Medium

    Provided loss-of-function evidence that POLD1 is required for proliferation, cell-cycle progression, and resistance to oxidative DNA damage.

    Evidence shRNA knockdown, BrdU incorporation, FACS, comet assay in HEK293

    PMID:26087769

    Open questions at the time
    • Overexpression had no effect, leaving dosage relationships unclear
    • Single cell line
  9. 2016 Medium

    Established POLD1 as essential for genome stability by linking its depletion to DNA breaks, impaired S-phase, and reduced origin firing.

    Evidence siRNA/shRNA knockdown with DNA damage markers, FACS, replication origin mapping

    PMID:27974823

    Open questions at the time
    • Mechanism connecting POLD1 loss to origin reduction not defined
    • Single lab
  10. 2016 Medium

    Uncovered a synthetic-lethal interaction between POLD1 and ATR, nominating POLD1-deficient tumors for ATR/CHK1-targeted therapy.

    Evidence Synthetic-lethal RNAi screen with pharmacological ATR/CHK1 inhibition and apoptosis assays

    PMID:26755646

    Open questions at the time
    • Mechanistic basis of dependency not yet dissected
    • Allele-specific effects untested at this stage
  11. 2019 Medium

    Connected POLD1 downregulation to replicative senescence through age-related decline in direct E2F1 promoter binding compounded by CpG methylation.

    Evidence ChIP, CpG methylation analysis, shRNA knockdown, reporter assays

    PMID:30895337

    Open questions at the time
    • Causal contribution of POLD1 loss to senescence vs correlation
    • Single model system
  12. 2020 High

    Showed that quantitatively reduced polymerase activity with intact proofreading produces a tissue-specific recessive phenotype, expanding the genotype–phenotype spectrum to nonsyndromic hearing loss.

    Evidence Compound-heterozygous genetics with recombinant in vitro polymerase and exonuclease activity assays

    PMID:31944473

    Open questions at the time
    • Why cochlear tissue is selectively vulnerable unexplained
    • Threshold of activity tolerated by other tissues undefined
  13. 2021 Medium

    Identified CTCF as a direct transcriptional activator of POLD1 whose age-related decline accelerates replicative senescence.

    Evidence ChIP, shRNA knockdown of CTCF and POLD1, overexpression, senescence assays

    PMID:33692996

    Open questions at the time
    • Interplay between CTCF and E2F1/methylation control not integrated
    • Single lab
  14. 2022 Medium

    Provided a molecular explanation for MDPL beyond replication, showing the p.Ser605del variant creates an aberrant FSLYP motif driving abnormal POLD1–TRF1 binding and telomere dysfunction.

    Evidence Molecular docking/dynamics with Co-IP in MDPL patient fibroblasts and PARP1 analysis

    PMID:41219970

    Open questions at the time
    • Functional consequence of TRF1 binding for telomere maintenance not directly measured
    • Single lab
  15. 2022 Medium

    An in vivo hypomorphic Pold1 mouse defined adequate POLD1-dependent proliferation as essential for gastrulation morphogenesis while sparing axial patterning.

    Evidence ENU mutagenesis, genetic mapping, in vivo developmental and proliferation analysis

    PMID:35876795

    Open questions at the time
    • Molecular basis of the D939Y hypomorphism not biochemically resolved
    • Relevance to human developmental phenotypes unclear
  16. 2023 High

    Revealed a polymerase-independent oncogenic function: POLD1 stabilizes MYC by competing with FBXW7 at the MB1 domain, forming a MYC–POLD1 positive feedback loop.

    Evidence Reciprocal Co-IP, ubiquitination and competitive binding assays, polymerase-dead mutant, xenografts

    PMID:37105989

    Open questions at the time
    • Whether this function operates in normal tissues unknown
    • Structural basis of MB1 competition not resolved
  17. 2023 High

    Pinpointed the DEDD catalytic core, confirming that the D402N substitution abolishes nuclease activity and generates POLD1-specific mutational signatures.

    Evidence Biochemical nuclease assay plus engineered cell-line mutational signature analysis

    PMID:38067377

    Open questions at the time
    • In vivo tumor consequences of D402N not directly demonstrated
    • Structural coordination details inferred
  18. 2024 High

    Established that exonuclease deficiency acts recessively at the cellular level, with hypermutation requiring somatic loss of the wild-type allele — reconciling subtle germline effects with explosive tumor mutation rates.

    Evidence Fibroblast colony mutation analysis, de novo mutation comparison, tumor WGS/WES, LOH analysis

    PMID:38658779

    Open questions at the time
    • Selective pressure driving wild-type allele loss not defined
    • Tissue tropism of resulting tumors unexplained
  19. 2024 High

    Defined the mechanistic basis of POLD1–ATR synthetic lethality using a specific engineered allele, showing R689W triggers compensatory ATR signaling and sensitizes cells to ATR/CHK1 inhibition.

    Evidence CRISPR/Cas9 knockin in DLD-1, ATR pathway markers, replication and survival assays, murine xenografts

    PMID:33144657

    Open questions at the time
    • Generalizability across diverse POLD1 alleles untested
    • Clinical translation not addressed
  20. 2025 Medium

    Identified post-transcriptional control of POLD1 by SNRPB-dependent splicing of intron 22, whose retention deletes the PCNA-interaction region and disables the enzyme, linking splicing to cancer proliferation.

    Evidence RNA-seq, intron-retention RT-PCR, knockdown/rescue, xenografts, miR-654-5p analysis

    PMID:39910288

    Open questions at the time
    • Whether splicing control operates outside endometrial cancer unknown
    • Single lab
  21. 2025 High

    Connected POLD1 to a pathological proliferation program, showing a p21–PCNA–POLD1 axis drives cardiomyocyte endoreplication and hypertrophy that can be reversed by targeting POLD1.

    Evidence Proximity ligation assay, proteomics, transgenic and pressure-overload mouse models, AAV overexpression

    PMID:40948130

    Open questions at the time
    • Upstream signals activating cardiac POLD1 endoreplication unclear
    • Translatability of POLD1 targeting in heart untested clinically
  22. 2025 Medium

    Placed POLD1 downstream of an infection-driven transcriptional axis, showing H. pylori-induced ACVR1 suppresses IRF3-mediated POLD1 transcription to cause DNA double-strand breaks.

    Evidence ChIP for IRF3 sites, luciferase, comet assay, organoids, INS-GAS mice, ACVR1 inhibitor

    PMID:39924917

    Open questions at the time
    • Direct contribution of POLD1 loss to gastric carcinogenesis not isolated
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How POLD1's polymerase-independent functions (MYC stabilization, cardiac endoreplication) are integrated with its canonical replication/proofreading roles, and what determines the striking tissue specificity of its disease phenotypes, remains unresolved.
  • No unified model linking dosage, allele type, and tissue vulnerability
  • Structural basis of non-catalytic protein interactions undetermined
  • Mechanism of allele-specific synthetic lethality across the genotype spectrum incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0003677 DNA binding 2 GO:0016787 hydrolase activity 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 3 R-HSA-73894 DNA Repair 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
FBXW7MYCP21PCNATRF1
Complex memberships
DNA polymerase delta

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Germline mutations in the proofreading (exonuclease) domain of POLD1 (e.g., p.Ser478Asn) cause defective correction of mispaired bases during DNA replication, leading to a base substitution mutator phenotype. Yeast functional assays confirmed that these mutations impair proofreading activity. Whole-genome sequencing, linkage/association analysis, yeast functional assays Nature genetics High 23263490
2013 A heterozygous single-codon in-frame deletion in POLD1 affecting the polymerase active site (p.Ser605del) abolishes DNA polymerase activity but only mildly impairs 3'-5' exonuclease activity, causing the MDPL multisystem disorder (lipodystrophy, deafness, mandibular hypoplasia, hypogonadism). Genomic sequencing, in vitro biochemical assay of polymerase and exonuclease activity on mutant protein Nature genetics High 23770608
1997 The human POLD1 promoter lacks a TATA box, contains two 11-bp direct repeats critical for promoter activity, and is activated by transcription factors Sp1 and Sp3 (but not Sp2) through these repeat sequences. Promoter activity is induced ~4-fold at the G1/S boundary, requiring the 11-bp repeats together with an E2F-like sequence. Transient transfection/luciferase reporter assays, DNase I footprinting, band-shift assays, Southwestern blot, UV cross-linking, cDNA expression library screening, Drosophila SL2 cotransfection The Journal of biological chemistry High 9030545
2001 Wild-type p53 transcriptionally represses POLD1 expression by competing with Sp1 for binding to the P4 site in the POLD1 promoter; tumor-derived p53 mutations abolish this repression. p53 suppresses Sp1-stimulated POLD1 promoter activity through loss of sequence-specific interaction at the overlapping P4 p53/Sp1-binding site. Northern blotting, tetracycline-regulated p53 expression system, transient cotransfection with luciferase reporter, gel shift (EMSA) assays The Journal of biological chemistry High 11375983
2012 PRMT7 interacts with the BRG1-based hSWI/SNF chromatin remodeling complex and methylates histone H2A Arg-3 and H4 Arg-3 at the POLD1 promoter, negatively regulating POLD1 expression. PRMT7 knockdown causes derepression of POLD1 and increased cell resistance to DNA-damaging agents; re-knockdown of POLD1 alone resensitizes cells to DNA damage, placing POLD1 as the critical downstream target. Co-immunoprecipitation, ChIP, shRNA knockdown, global gene expression analysis, DNA damage sensitivity assays The Journal of biological chemistry High 22761421
2016 Depletion of POLD1 (the catalytic subunit of Pol δ) causes increased DNA breaks, S-phase progression impairment, chromosome abnormalities, and reduction in active replication origins, establishing POLD1 as essential for maintaining genome stability and proper S-phase progression. siRNA/shRNA knockdown, DNA damage markers, FACS cell cycle analysis, replication origin mapping Scientific reports Medium 27974823
2016 POLD1 depletion in ATR-deficient cancer cells causes caspase-dependent apoptosis without preceding cell cycle arrest, accompanied by increased DNA damage and impaired DNA repair, establishing a synthetic lethal interaction between ATR and POLD1. Synthetic lethal RNAi screen (288 DNA repair genes), pharmacological ATR/CHK1 inhibitors, POLD1 siRNA knockdown, apoptosis assays, DNA damage markers Oncotarget Medium 26755646
2009 A CDE/CHR element in the POLD1 promoter is required for cell cycle-dependent transcriptional regulation; mutation of this element upregulates promoter activity and abrogates regulation by E2F1 and p21. At least three DNA-protein complexes bind to this element. Luciferase reporter constructs with promoter mutations, EMSA Science in China. Series C, Life sciences Medium 19557333
2019 E2F1 binds directly to the POLD1 promoter (particularly at CpG island 3), and its age-related decline combined with increased promoter methylation at CpG 36 attenuates E2F1 binding affinity, leading to POLD1 downregulation in replicative senescence. shRNA knockdown of E2F1 induces senescence characteristics. ChIP, CpG island methylation analysis, shRNA knockdown, luciferase reporter Cellular and molecular life sciences : CMLS Medium 30895337
2021 CTCF binds to two sites in the POLD1 promoter region; age-related decline in CTCF reduces its binding to the POLD1 promoter, downregulating POLD1 expression and accelerating replicative senescence. ChIP, shRNA knockdown of CTCF and POLD1, overexpression constructs, senescence assays Frontiers in cell and developmental biology Medium 33692996
2016 p53 inhibits POLD1 promoter methylation indirectly by downregulating Sp1-induced DNMT1 activity; p53 overexpression reduces both Sp1 and DNMT1 levels, leading to decreased POLD1 methylation and reduced p125 expression in breast cancer cells. Western blot, qRT-PCR, Sp1/p53 co-immunoprecipitation, methylation analysis in MCF-7 cells OncoTargets and therapy Low 27022290
2023 POLD1 stabilizes MYC by directly binding to the MYC homology box 1 (MB1) domain, competing with the E3 ligase FBXW7 and thereby attenuating FBXW7-mediated ubiquitination and degradation of MYC. POLD1 also forms a complex with MYC to promote MYC transcriptional activity, while MYC in turn upregulates POLD1 expression, forming a positive feedback loop. This function is independent of POLD1's DNA polymerase activity. Co-immunoprecipitation, ubiquitination assay, competitive binding assay, shRNA/siRNA knockdown, overexpression, transcriptional reporter, xenograft model Nature communications High 37105989
2015 POLD1 downregulation by shRNA suppresses cell proliferation, cell cycle progression, and DNA synthesis in HEK293 cells, and increases DNA damage after H2O2 treatment; overexpression had no significant effect on these processes. shRNA knockdown, overexpression plasmid, cell proliferation assay, cell cycle FACS, BrdU incorporation, comet assay BMC biochemistry Medium 26087769
2018 SIRT1 promotes POLD1/p125 expression in breast cancer cells via suppression of p53; SIRT1 knockdown increases p53 expression and decreases POLD1 expression, reducing proliferation, migration, and invasion of MCF-7 cells, while SIRT1 overexpression has the opposite effect. shRNA knockdown, overexpression, Western blot, immunohistochemistry, proliferation/migration/invasion assays Biochemical and biophysical research communications Low 29807012
2020 POLD1 variants causing reduced polymerase activity (e.g., p.Gly1100Arg reducing activity by 30-40%) but normal exonuclease activity can cause autosomal recessive nonsyndromic sensorineural hearing loss when combined with a null allele, establishing that significantly reduced polymerase δ activity with normal proofreading leads to a tissue-specific phenotype. Genetic analysis (compound heterozygous variants), recombinant protein expression, in vitro polymerase activity assay, in vitro exonuclease activity assay, cell extract polymerase activity measurement Human mutation High 31944473
2025 SNRPB promotes efficient splicing of POLD1 intron 22; SNRPB knockdown causes retention of intron 22, creating a premature termination codon that eliminates amino acids 941-1107 including the PCNA-interaction site essential for POLD1 enzyme activity, thereby reducing POLD1 expression and inhibiting endometrial cancer cell proliferation and metastasis. RNA sequencing, RT-PCR for intron retention, shRNA knockdown, overexpression rescue, xenograft models, miR-654-5p functional analysis Experimental & molecular medicine Medium 39910288
2025 p21 binds to PCNA, reducing PCNA binding to POLD1, thereby inhibiting POLD1-mediated cardiomyocyte endoreplication and hypertrophic growth. Direct targeting of PCNA or POLD1 prevents cardiomyocyte DNA synthesis and hypertrophic growth in murine models of hypertrophic cardiomyopathy. Proximity ligation assay, proteomics, flow cytometry, immunohistochemistry, transgenic mouse models, AAV-mediated overexpression, transverse aortic constriction model Circulation research High 40948130
2025 H. pylori infection upregulates ACVR1, which inhibits IRF3-mediated transcriptional activation of POLD1, reducing POLD1 expression and causing DNA double-strand break accumulation; ChIP identified IRF3-binding sites in the POLD1 promoter. Western blot, qRT-PCR, immunofluorescence, luciferase assay, ChIP, comet assay, patient-derived gastric organoids, INS-GAS transgenic mice, ACVR1 inhibitor treatment Gut microbes Medium 39924917
2022 The recurrent MDPL mutation p.Ser605del in POLD1 alters short linear motifs and creates an FSLYP motif that mediates abnormal interaction with TRF1 (a telomeric protein); the stronger POLD1(Ser605del)-TRF1 binding was confirmed by co-immunoprecipitation in MDPL patient fibroblasts, and PARP1 dysregulation was observed, suggesting a link between this POLD1 variant and telomere biology contributing to premature aging. Molecular docking, molecular dynamics simulations, co-immunoprecipitation, Western blot, RT-qPCR in patient-derived fibroblasts, X-ray irradiation challenge Human genomics Medium 41219970
2024 The POLD1R689W variant causes compensatory ATR pathway activation and impaired DNA replication. CRISPR/Cas9-generated heterozygous POLD1-knockout clones expressing only R689W showed strongly decreased cell survival upon ATR or CHK1 inhibitor treatment in vitro and inhibited murine xenograft tumor growth in vivo, confirming the synthetic lethal relationship of POLD1 deficiency with ATR/CHK1 inhibition. CRISPR/Cas9 knockin in DLD-1 cells, ATR pathway activation markers, DNA replication assays, cell survival assays, murine xenograft in vivo treatment Scientific reports High 33144657
2023 Biochemical assay confirmed that the POLD1 p.D402N variant (charge-discordant substitution in the DEDD motif) causes loss of nuclease activity; the DEDD motif (D316, E318, D402, D515) coordinates two magnesium cations essential for exonuclease catalysis. Overexpression of POLD1(D402N) in cell lines generated POLD1-specific mutational signatures, confirming functional proofreading deficiency. In silico analysis, biochemical nuclease activity assay, whole-exome sequencing of patient tumor, engineered cell lines with POLD1(D402N) overexpression and mutational signature analysis Cancers High 38067377
2022 A hypomorphic mouse mutation D939Y in Pold1 (catalytic subunit of DNA polymerase δ) discovered by ENU mutagenesis impairs cell proliferation during gastrulation, resulting in reduced embryo size and severe morphogenetic defects while leaving anterior-posterior patterning unperturbed, demonstrating that adequate POLD1-dependent cell proliferation is required for proper morphogenesis during gastrulation. ENU mutagenesis screen, genetic mapping, in vivo mouse developmental analysis, cell proliferation quantification Biology open Medium 35876795
2024 Tumors developing in individuals heterozygous for POLD1 exonuclease domain mutations (e.g., L474P) have extremely high mutation rates (>100 mut/Mb) associated with signature SBS10d, whereas patient-derived fibroblasts and germline transmission show only subtle mutation rate increases. Tumorigenesis involves somatic inactivation of the wild-type POLD1 allele, establishing that exonuclease deficiency of polymerase delta has a recessive effect on mutation rate. Mutational pattern analysis of patient-derived fibroblast colonies, de novo mutation analysis by parent-offspring comparison, whole-genome/exome sequencing of tumors, loss-of-heterozygosity analysis European journal of human genetics : EJHG High 38658779
2004 Exogenous wild-type POLD1 expression did not significantly decrease the spontaneous mutation rate at the HPRT locus in DLD-1 colon cancer cells (which lack wild-type POLD1 alleles), while wild-type MSH6 expression reduced mutation rates >4-fold, indicating that MSH6 rather than POLD1 mutations primarily drive the mutator phenotype in DLD-1 cells. POLD1 genotyping by sequencing, stable transfection with wild-type MSH6 or POLD1, HPRT mutation frequency assay International journal of oncology Medium 14767555

Source papers

Stage 0 corpus · 97 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nature genetics 777 23263490
2015 POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance. Genetics in medicine : official journal of the American College of Medical Genetics 202 26133394
2013 An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nature genetics 145 23770608
2013 CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 140 23408870
2014 New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Human molecular genetics 123 24501277
2016 POLD1: Central mediator of DNA replication and repair, and implication in cancer and other pathologies. Gene 114 27320729
2012 Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase δ catalytic subunit gene, POLD1. The Journal of biological chemistry 112 22761421
2015 Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers. European journal of human genetics : EJHG 107 26648449
2020 Role of POLE and POLD1 in familial cancer. Genetics in medicine : official journal of the American College of Medical Genetics 103 32792570
2022 POLE/POLD1 mutation and tumor immunotherapy. Journal of experimental & clinical cancer research : CR 97 35780178
2024 Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Annals of oncology : official journal of the European Society for Medical Oncology 65 38777726
2022 Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity. Nature genetics 61 35817971
2001 Transcriptional regulation of the human DNA polymerase delta catalytic subunit gene POLD1 by p53 tumor suppressor and Sp1. The Journal of biological chemistry 61 11375983
1997 The human POLD1 gene. Identification of an upstream activator sequence, activation by Sp1 and Sp3, and cell cycle regulation. The Journal of biological chemistry 61 9030545
2021 POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes. Oncogene 58 34363023
2017 Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Integrating the literature on hereditary diffuse leukoencephalopathy with spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD). Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 58 29122458
2015 POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome. Human mutation 55 26172944
2016 Roles of human POLD1 and POLD3 in genome stability. Scientific reports 49 27974823
2021 Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression. Frontiers in oncology 48 33747905
2014 Identification of a novel mutation in the polymerase delta 1 (POLD1) gene in a lipodystrophic patient affected by mandibular hypoplasia, deafness, progeroid features (MDPL) syndrome. Metabolism: clinical and experimental 48 25131834
2019 Comprehensive analysis of POLE and POLD1 Gene Variations identifies cancer patients potentially benefit from immunotherapy in Chinese population. Scientific reports 46 31673068
2017 Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL). Metabolism: clinical and experimental 46 28521875
2017 Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. Genetics in medicine : official journal of the American College of Medical Genetics 44 29120461
2017 POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer. Oncotarget 43 28423643
2016 Shared active site architecture between archaeal PolD and multi-subunit RNA polymerases revealed by X-ray crystallography. Nature communications 43 27548043
2018 SIRT1 promotes proliferation, migration, and invasion of breast cancer cell line MCF-7 by upregulating DNA polymerase delta1 (POLD1). Biochemical and biophysical research communications 41 29807012
2017 Definitive diagnosis of mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome caused by a recurrent de novo mutation in the POLD1 gene. Endocrine journal 41 29199204
2015 Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas. Gynecologic oncology 36 26748215
2023 DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC. Nature communications 34 37105989
2016 A synthetic lethal screen identifies ATR-inhibition as a novel therapeutic approach for POLD1-deficient cancers. Oncotarget 33 26755646
2015 Human POLD1 modulates cell cycle progression and DNA damage repair. BMC biochemistry 33 26087769
2021 Distinctive genomic characteristics in POLE/POLD1-mutant cancers can potentially predict beneficial clinical outcomes in patients who receive immune checkpoint inhibitor. Annals of translational medicine 29 33569431
2019 Structure of the DP1-DP2 PolD complex bound with DNA and its implications for the evolutionary history of DNA and RNA polymerases. PLoS biology 29 30657780
2019 E2F1 mediates the downregulation of POLD1 in replicative senescence. Cellular and molecular life sciences : CMLS 28 30895337
1999 Specific interaction between DNA polymerase II (PolD) and RadB, a Rad51/Dmc1 homolog, in Pyrococcus furiosus. Nucleic acids research 28 10572168
2017 Hybrid origin of Asian aspermic Fasciola flukes is confirmed by analyzing two single-copy genes, pepck and pold. The Journal of veterinary medical science 27 29187710
1995 Structure of the gene for the catalytic subunit of human DNA polymerase delta (POLD1). Genomics 24 7490075
2018 Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene. DNA and cell biology 21 30388038
2023 Recommendations for the classification of germline variants in the exonuclease domain of POLE and POLD1. Genome medicine 20 37848928
2021 CTCF Mediates Replicative Senescence Through POLD1. Frontiers in cell and developmental biology 20 33692996
2016 p53 inhibits the expression of p125 and the methylation of POLD1 gene promoter by downregulating the Sp1-induced DNMT1 activities in breast cancer. OncoTargets and therapy 20 27022290
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
2018 POLD1 and POLE Gene Mutations in Jewish Cohorts of Early-Onset Colorectal Cancer and of Multiple Colorectal Adenomas. Diseases of the colon and rectum 19 30086056
2021 Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity. Aging 18 33618333
2017 Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort. Scientific reports 18 28533537
2022 Investigation of Functional Synergism of CENPF and FOXM1 Identifies POLD1 as Downstream Target in Hepatocellular Carcinoma. Frontiers in medicine 17 35865168
2019 Germline POLE and POLD1 proofreading domain mutations in endometrial carcinoma from Middle Eastern region. Cancer cell international 16 31866764
2023 Prospects of POLD1 in Human Cancers: A Review. Cancers 15 36980791
2017 The first Japanese patient with mandibular hypoplasia, deafness, progeroid features and lipodystrophy diagnosed via POLD1 mutation detection. Human genome variation 15 28791128
2024 Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer. JAMA network open 14 38231514
2018 Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia. Medicine 14 29768346
2018 A De Novo POLD1 Mutation Associated With Mandibular Hypoplasia, Deafness, Progeroid Features, and Lipodystrophy Syndrome in a Family With Werner Syndrome. Journal of investigative medicine high impact case reports 14 30023403
2024 A phase II clinical trial of toripalimab in advanced solid tumors with polymerase epsilon/polymerase delta (POLE/POLD1) mutation. Signal transduction and targeted therapy 13 39218995
2020 POLE and POLD1 germline exonuclease domain pathogenic variants, a rare event in colorectal cancer from the Middle East. Molecular genetics & genomic medicine 13 32567205
2020 POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer. Endocrine connections 12 32992294
2019 POLD1 deficiency is involved in cognitive function impairment in AD patients and SAMP8 mice. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 12 30978525
2013 Effect of Smilax china L.-containing serum on the expression of POLD1 mRNA in human hepatocarcinoma SMMC-7721 cells. Experimental and therapeutic medicine 12 24137319
2009 Identification and functional analysis of a CDE/CHR element in the POLD1 promoter. Science in China. Series C, Life sciences 11 19557333
2025 Helicobacter pylori infection induces DNA double-strand breaks through the ACVR1/IRF3/POLD1 signaling axis to drive gastric tumorigenesis. Gut microbes 10 39924917
2024 A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer. The oncologist 10 38776551
2023 POLD1 DEDD Motif Mutation Confers Hypermutation in Endometrial Cancer and Durable Response to Pembrolizumab. Cancers 10 38067377
2020 The POLD1R689W variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors. Scientific reports 10 33144657
2022 Scrutinizing Deleterious Nonsynonymous SNPs and Their Effect on Human POLD1 Gene. Genetics research 9 35620275
2020 POLD1 variants leading to reduced polymerase activity can cause hearing loss without syndromic features. Human mutation 9 31944473
2019 Low frequency of POLD1 and POLE exonuclease domain variants in patients with multiple colorectal polyps. Molecular genetics & genomic medicine 9 30827058
2024 Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells. European journal of human genetics : EJHG 8 38658779
2025 Targeting the splicing factor SNRPB inhibits endometrial cancer progression by retaining the POLD1 intron. Experimental & molecular medicine 7 39910288
2023 Rare germline variants in POLE and POLD1 encoding the catalytic subunits of DNA polymerases ε and δ in glioma families. Acta neuropathologica communications 7 37990341
2022 Mild MDPL in a patient with a novel de novo missense variant in the Cys-B region of POLD1. European journal of human genetics : EJHG 7 35590056
2025 Beyond proofreading: POLD1 mutations as dynamic orchestrators of genomic instability and immune evasion in cancer. Frontiers in immunology 6 40661943
2023 From cue to meaning: The involvement of POLD1 gene in DNA replication, repair and aging. Mechanisms of ageing and development 6 36764464
2023 Integrating POLE/POLD1 mutated for immunotherapy treatment planning of advanced stage non-small cell lung cancer. Thoracic cancer 6 37345618
2022 A likely pathogenic POLD1 variant associated with mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome in a Chinese patient. BMC medical genomics 6 36280868
2018 Correction: Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. Genetics in medicine : official journal of the American College of Medical Genetics 6 29388942
2017 Characterization of a novel POLD1 missense founder mutation in a Spanish population. The journal of gene medicine 6 28306219
2017 Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel-Hypermutated Cancer Genome and Comutation of POLD1 and MLH1. JCO precision oncology 5 30009279
2004 Effect of exogenous MSH6 and POLD1 expression on the mutation rate of the HPRT locus in a human colon cancer cell line with mutator phenotype, DLD-1. International journal of oncology 5 14767555
2025 Targeting Cardiomyocyte PCNA and POLD1 Prevents Pathologic Myocardial Hypertrophy. Circulation research 4 40948130
2024 POLD1 Is Required for Cell Cycle Progression by Overcoming DNA Damage in Malignant Pleural Mesothelioma. Cancer genomics & proteomics 4 38423601
2024 Targeting POLD1 to suppress the proliferation and migration of breast cancer MDA-MB-231 cell lines by downregulation of SIRT1. Toxicology research 4 39036524
2022 IGF-1 Accelerates Cell Aging by Inhibiting POLD1 Expression. Biomedical and environmental sciences : BES 4 36443251
2021 Child to adulthood clinical description of MDPL syndrome due to a novel variant in POLD1. European journal of medical genetics 3 34517090
2020 Preliminary study on the function of the POLD1 (CDC2) EXON2 c.56G>A mutation. Molecular genetics & genomic medicine 3 32432416
2025 PolED: a manually curated database of functional studies of POLE and POLD1 variants reported in humans. Database : the journal of biological databases and curation 2 41263451
2023 Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome. Frontiers in molecular biosciences 2 36756361
2023 Case Report: Cancer spectrum and genetic characteristics of a de novo germline POLD1 p.L606M variant-induced polyposis syndrome. Frontiers in oncology 2 37746257
2022 A hypomorphic mutation in Pold1 disrupts the coordination of embryo size expansion and morphogenesis during gastrulation. Biology open 2 35876795
2021 A novel POLD1 pathogenic variant identified in two families with a cancer spectrum mimicking Lynch syndrome. European journal of medical genetics 2 34954152
2025 The germline POLD1 c.1420 C > A (p.Leu474Ile) variant segregates with endometrial cancer, colorectal cancer and colonic polyps demonstrating hypermutation and defective POLD1 mutational signatures. Familial cancer 1 41212251
2017 Detection of Allelic Variants of the POLE and POLD1 Genes in Colorectal Cancer Patients. Balkan journal of medical genetics : BJMG 1 29876237
2026 Genotype-Phenotype Heterogeneity Among Patients with Lipodystrophy Harboring Rare POLD1 Variants. The Journal of clinical endocrinology and metabolism 0 41742372
2026 Immune checkpoint inhibitors in POLE/POLD1 proofreading-deficient CRC: from molecular basis to clinical practice and future directions. Immunotherapy 0 42017297
2026 Successful Treatment of POLD1 Deficiency With HSCT: Report of Two Years' Experience. Pediatric transplantation 0 42104577
2026 Endoscopic and imaging evaluations of neoadjuvant immunotherapy in patients with locally advanced colorectal cancer with dMMR/MSI-H or POLE/POLD1 mutation. European radiology 0 42128946
2025 Structural and functional impact of the POLD1 Ser605del variant in MDPL syndrome: insights from protein-protein interactions. Human genomics 0 41219970
2025 Case Report: Expansion of the POLD1-related polymerase proofreading-associated polyposis spectrum: first report of duodenal adenocarcinomas and characterization of two likely pathogenic variants. Frontiers in oncology 0 41487566
2023 Altered immunoexpression of DNA polymerase delta 1 catalytic subunit (POLD1) in colorectal cancer. Contemporary oncology (Poznan, Poland) 0 38239863

Missed literature

Know a paper Affinage missed for POLD1? Flag it for the maintainers and the community.

No submissions yet.