Affinage

POLH

DNA polymerase eta · UniProt Q9Y253

Length
713 aa
Mass
78.4 kDa
Annotated
2026-06-10
40 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

POLH encodes human DNA polymerase eta, a damage-bypass replication enzyme of the UmuC/DinB/Rev1 family that performs translesion synthesis (TLS) past UV-induced lesions; loss of POLH function underlies xeroderma pigmentosum variant (XP-V), and all XP-V cells examined carry POLH mutations (PMID:10385124). The purified ~54 kDa monomeric polymerase replicates cyclobutane pyrimidine dimer (CPD)-containing templates, requires Mg2+, is aphidicolin- and ddTTP-resistant, and accurately inserts dATP opposite a di-thymine lesion, accounting for its error-free bypass of UV photoproducts (PMID:10369688). When POLH is absent, error-prone backup TLS across TT CPDs is carried out by DNA polymerase zeta cooperating with polymerases kappa and iota, with zeta and kappa additionally protecting cells from UV cytotoxicity independently of nucleotide excision repair (PMID:19564618). Beyond UV photoproducts, pol eta bypasses cisplatin lesions, and germline missense variants that reduce its catalytic efficiency (kcat/Km for dATP insertion opposite CTD lesions) or destabilize the protein fail to rescue UV- and cisplatin-sensitivity in POLH-deficient cells (PMID:36982269, PMID:40334807). POLH also has roles beyond replicative lesion bypass: it generates A:T and C-to-G/G-to-C transversions during immunoglobulin somatic hypermutation through a pathway involving non-catalytic REV1 and operating independently of UNG (PMID:22223762, PMID:22960197), and POLH-deficient mice develop a metabolic syndrome driven by DNA-damage-associated, p53-dependent adipocyte senescence (PMID:26240351). POLH expression is post-transcriptionally controlled by alternative polyadenylation, with a short 3'UTR isoform escaping miR-619 repression to drive high pol eta levels and cisplatin resistance in cancer cells (PMID:31064846).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Established that the gene defective in XP-V encodes a translesion polymerase, answering why XP-V cells cannot replicate UV-damaged DNA.

    Evidence Purification of a ~54 kDa monomeric polymerase from HeLa cells, cell-free TLS assay, complementation of XP-V extracts, and POLH mutation analysis across XP-V lines

    PMID:10369688 PMID:10385124

    Open questions at the time
    • Structural basis of accurate di-thymine bypass not resolved at atomic level
    • Regulation of recruitment to replication forks not addressed
  2. 2009 Medium

    Defined the backup machinery that operates when pol eta is missing, explaining the error-prone, mutagenic outcome of UV bypass in XP-V cells.

    Evidence Genetic epistasis with siRNA knockdown of TLS polymerases in XP-V patient cells, with cytotoxicity and mutagenesis readouts

    PMID:19564618

    Open questions at the time
    • Single lab
    • Biochemical division of labor between zeta, kappa, and iota not reconstituted
  3. 2012 Medium

    Showed POLH contributes to antibody diversification through pathways distinct from its replicative TLS role, broadening its physiological function.

    Evidence REV1AA Polh(-/-) and Ung(-/-)Polh(-/-) double-mutant mouse genetics with Ig gene hypermutation spectrum sequencing

    PMID:22223762 PMID:22960197

    Open questions at the time
    • Molecular basis of REV1–POLH cooperation for transversions undefined
    • Single lab
  4. 2015 Medium

    Linked POLH loss to a systemic phenotype, placing the polymerase upstream of p53-dependent cellular senescence in metabolic tissue.

    Evidence Pol eta knockout mice with metabolic phenotyping, DNA-damage/senescence markers, and pharmacological p53 inhibition rescue

    PMID:26240351

    Open questions at the time
    • Tissue-specific lesion driving senescence not identified
    • Single lab
  5. 2019 Medium

    Identified post-transcriptional control of POLH expression as a determinant of chemoresistance.

    Evidence APA site mapping, 3'UTR reporter assays, miR-619 perturbation, and cisplatin sensitivity assays in cancer cell lines

    PMID:31064846

    Open questions at the time
    • Upstream regulation of APA choice unknown
    • Single lab
  6. 2023 Medium

    Built a functional assay framework distinguishing pathogenic from benign POLH variants by coupling kinetics to cellular rescue.

    Evidence Recombinant kinetics on CTD templates plus CRISPR knockout complementation with UV/cisplatin sensitivity in 2023 and 2025 studies

    PMID:36982269 PMID:40334807

    Open questions at the time
    • Genotype–phenotype mapping to XP-V severity incomplete
    • Protein-stability versus catalytic mechanisms not always separable
    • Single lab
  7. 2021 Medium

    Provided the first liganded POLH crystal structures, opening structure-guided inhibitor development against the polymerase.

    Evidence Fragment-based drug discovery with X-ray crystallography and in vitro biochemical inhibition assays

    PMID:34900730

    Open questions at the time
    • Inhibitor specificity over other Y-family polymerases not established
    • Cellular efficacy not demonstrated
  8. 2025 Low

    Raised a non-canonical transcriptional role for the POLH ortholog at retrotransposons, distinct from replicative lesion bypass.

    Evidence Drosophila genetic screen, CUT&Tag, mass spectrometry, proximity ligation, and RNA Pol II ChIP-seq

    PMID:40966519

    Open questions at the time
    • Findings in Drosophila, not replicated in mammalian systems
    • Mechanistic link between PolH and RNA Pol II occupancy unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How pol eta is selectively recruited to and exchanged at sites of distinct lesion types, and whether its transcriptional/retrotransposon role exists in mammals, remain open.
  • No mammalian validation of transcriptional role
  • Lesion-specific polymerase switching mechanism uncharacterized in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 4 GO:0016740 transferase activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-73894 DNA Repair 3 R-HSA-69306 DNA Replication 2
Partners
REV1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 POLH encodes human DNA polymerase eta, a homologue of yeast Rad30, which belongs to the UmuC/DinB/Rev1 family of damage-bypass replication proteins. Recombinant human DNA polymerase eta directly bypasses UV-induced thymine dimers in translesion DNA synthesis, correcting the replication defect in XP-V cell extracts. All XP-V cells examined carried mutations in the POLH gene. Protein purification from HeLa cells, cell-free translesion synthesis assay, complementation of XP-V extracts with recombinant protein, mutation analysis of XP-V cell lines Nature High 10385124
1999 The XPV-complementing protein purified from HeLa cells is a ~54 kDa monomeric DNA polymerase that replicates cyclobutane pyrimidine dimer (CPD)-containing DNA templates. Activity requires MgCl2, is sensitive to NEM, moderately sensitive to KCl, resistant to aphidicolin and ddTTP, not stimulated by PCNA, and incorporates only dATP opposite a di-thymine lesion. The monomeric 54 kDa polypeptide sediments at 3.5S. Protein purification from HeLa cells, biochemical characterization of polymerase activity, glycerol density gradient sedimentation, cell-free complementation assay with XP-V extracts The EMBO journal High 10369688
2009 In XP-V (POLH-deficient) cells, error-prone translesion synthesis across TT CPD lesions is carried out by a backup pathway in which DNA polymerase zeta cooperates with DNA polymerases kappa and iota. DNA polymerases zeta and kappa (but not iota) also protect XPV cells against UV cytotoxicity independently of nucleotide excision repair, establishing a genetic epistasis relationship among TLS polymerases. Genetic epistasis in XP-V patient cells, siRNA knockdown of TLS polymerases, UV cytotoxicity and mutagenesis assays Proceedings of the National Academy of Sciences of the United States of America Medium 19564618
2012 Genetic interaction analysis in REV1AA Polh(-/-) double-mutant mice shows that POLH is required for the generation of C-to-G and G-to-C transversions during Ig gene somatic hypermutation that persist in REV1-catalytic-activity-deficient mice, revealing an alternative TLS pathway mediated by non-catalytic REV1 and POLH for generating these transversions. Double-mutant mouse genetics (REV1AA Polh(-/-)), Ig gene hypermutation sequencing in germinal center B cells, comparison to single mutants International immunology Medium 22223762
2012 In Ung(-/-)Polh(-/-) double-mutant mice, POLH deficiency did not affect the frequency or pattern of C:G mutations during Ig gene hypermutation, and UNG deficiency did not affect A:T mutation frequency or patterns, demonstrating that UNG and POLH operate in independent, non-overlapping pathways targeting distinct U:G lesions generated at different cell cycle phases. Double-mutant mouse genetics (Ung(-/-)Polh(-/-)), Ig gene hypermutation sequencing, comparison to single mutants Molecular immunology Medium 22960197
2015 POLH deficiency in mice causes obesity, visceral fat accumulation, hepatic steatosis, hyperinsulinemia, and glucose intolerance associated with increased DNA damage and cellular senescence (elevated ATM, γH2AX, PARP-1, p53, p16Ink4a, p21, SA-β-gal) in adipose tissue. Pharmacological inhibition of p53 with pifithrin-α reduced adipocyte senescence and attenuated metabolic abnormalities, placing POLH upstream of p53-mediated adipocyte senescence. Pol η knockout mice, metabolic phenotyping, DNA damage markers (immunostaining, western blot), pharmacological rescue with p53 inhibitor pifithrin-α, antioxidant treatment (NAC, metformin) Proceedings of the National Academy of Sciences of the United States of America Medium 26240351
2019 Alternative polyadenylation (APA) of POLH produces three major transcripts with different 3'UTR lengths (427, 2516, and 6245 nt). The short 427-nt 3'UTR transcript escapes miR-619-mediated repression and is responsible for high POLH protein expression in cisplatin-resistant cancer cells. Loss of the short transcript sensitizes cells to cisplatin. 3'UTR reporter assays, miRNA overexpression, APA site mapping, siRNA knockdown, cisplatin sensitivity assays in lung and bladder cancer cell lines Cancer research Medium 31064846
2021 X-ray crystal structures of small drug-like fragment compounds bound to POLH were solved (first reported crystal structures with bound inhibitors), enabling identification of binding sites on the polymerase as starting points for inhibitor development. Medicinal chemistry optimization produced inhibitors with functional activity in an in vitro biochemical assay. Fragment-based drug discovery, X-ray crystallography of POLH with bound fragments, in vitro biochemical polymerase inhibition assay Frontiers in oncology Medium 34900730
2023 Three POLH germline missense variants (C34W, I147N, R167Q) showed 4- to 14-fold reductions in specificity constants (kcat/Km) for dATP insertion opposite CTD lesions and failed to rescue UV- and cisplatin-sensitivity in POLH-knockout cells, identifying these as functionally defective variants. Two XPV-pathogenic mutants (R93P, G263V) and an active-site double mutant (D115A/E116A) also failed to rescue, validating the assay system. Recombinant protein expression, steady-state kinetics with CTD-containing templates, CRISPR/Cas9 POLH-knockout cell complementation assay, UV and cisplatin sensitivity assays International journal of molecular sciences Medium 36982269
2025 Four POLH germline variants (R81C, F17S, C227Y, R356X) impair pol η function: F17S, C227Y, and R356X showed 3- to 5000-fold reductions in kcat/Km for dATP insertion opposite CTD in vitro; R81C protein was undetectable in transfected cells (protein instability). CRISPR knock-in of R81C caused reduced pol η protein expression and increased cisplatin sensitivity. All four variants failed to rescue UV- and cisplatin-sensitivity in POLH-deficient cells. Recombinant protein kinetics, CRISPR/Cas9 knock-in and knockout in HEK293T cells, complementation assay, western blot, UV and cisplatin sensitivity assays Chemico-biological interactions Medium 40334807
2014 Site-directed mutagenesis of POLH at Y52E reduced the capacity of pol η to bypass UV-induced CPD lesions in HaCaT keratinocytes, as measured by slower CPD clearance and lower cell viability recovery after UVB irradiation compared to wild-type POLH. Site-directed mutagenesis (Y52E), transfection into HaCaT cells, CPD immunodetection, MTT cell viability assay The West Indian medical journal Low 25429473
2025 In Drosophila, PolH (ortholog of human POLH) and Rev1 are interacting partners that localize to active LTR-retrotransposons and safeguard RNA Polymerase II occupancy at these loci, promoting their transcription. Rev1 associates with RNA Pol II as shown by mass spectrometry and proximity ligation assay; CUT&Tag shows enrichment of PolH at LTR-retrotransposons. Genetic screen in Drosophila, CUT&Tag, mass spectrometry, proximity ligation assay, RNA Pol II ChIP-sequencing Nucleic acids research Low 40966519

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 1125 10385124
1999 Xeroderma pigmentosum variant (XP-V) correcting protein from HeLa cells has a thymine dimer bypass DNA polymerase activity. The EMBO journal 379 10369688
2009 DNA polymerase zeta cooperates with polymerases kappa and iota in translesion DNA synthesis across pyrimidine photodimers in cells from XPV patients. Proceedings of the National Academy of Sciences of the United States of America 104 19564618
2015 Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities. Proceedings of the National Academy of Sciences of the United States of America 68 26240351
2000 Genomic structure, chromosomal localization and identification of mutations in the xeroderma pigmentosum variant (XPV) gene. Oncogene 48 11032022
2019 A PolH Transcript with a Short 3'UTR Enhances PolH Expression and Mediates Cisplatin Resistance. Cancer research 40 31064846
2014 C-reactive protein and depression in persons with Human Immunodeficiency Virus infection: the Positive Living with HIV (POLH) Study. Brain, behavior, and immunity 40 24929193
2009 Variants of the xeroderma pigmentosum variant gene (POLH) are associated with melanoma risk. European journal of cancer (Oxford, England : 1990) 37 19477635
1996 The role of the AcMNPV 25K gene, "FP25," in baculovirus polh and p10 expression. Virology 37 8941320
2014 Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations. Human mutation 36 24130121
1998 Bypass of a site-specific cis-Syn thymine dimer in an SV40 vector during in vitro replication by HeLa and XPV cell-free extracts. Biochemistry 30 9609718
2012 Analysis of mice deficient in both REV1 catalytic activity and POLH reveals an unexpected role for POLH in the generation of C to G and G to C transversions during Ig gene hypermutation. International immunology 18 22223762
2007 The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin. International journal of molecular medicine 16 17334634
2021 Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH). Frontiers in oncology 15 34900730
2015 Serum Zinc Concentration and C-Reactive Protein in Individuals with Human Immunodeficiency Virus Infection: the Positive Living with HIV (POLH) Study. Biological trace element research 15 26429417
2013 A novel POLH mutation causes XP-V disease and XP-V tumor proneness may involve imbalance of numerous DNA polymerases. Oncology letters 13 24260050
2013 Identification of a novel nonsense mutation in POLH in a Chinese pedigree with xeroderma pigmentosum, variant type. International journal of medical sciences 8 23630442
2012 Analysis of Ig gene hypermutation in Ung(-/-)Polh(-/-) mice suggests that UNG and A:T mutagenesis pathway target different U:G lesions. Molecular immunology 7 22960197
1999 Cancer protection in xeroderma pigmentosum variant (XP-V). Anticancer research 7 10472330
2017 Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the POLH gene. American journal of medical genetics. Part A 6 28688171
2022 XPC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazil. Frontiers in genetics 5 35111200
2016 Dietary B Vitamins and Serum C-Reactive Protein in Persons With Human Immunodeficiency Virus Infection: The Positive Living With HIV (POLH) Study. Food and nutrition bulletin 5 27370977
2023 Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells. International journal of molecular sciences 3 36982269
2021 Xeroderma pigmentosum variant: squamous cell carcinoma of the lower lip harboring exon 11 mutation of POLH. Oral surgery, oral medicine, oral pathology and oral radiology 3 34030998
2020 Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia. Molecular genetics & genomic medicine 3 32935933
2016 miR-20b downregulates polymerases κ and θ in XP-V tumor cells. Oncology letters 3 27313696
2022 Actin Contributes to the Hyperexpression of Baculovirus Polyhedrin (polh) and p10 as a Component of Transcription Initiation Complex (TIC). Viruses 2 35062357
2025 Translesion DNA polymerases Rev1 and PolH promote LTR-retrotransposon transcription by safeguarding Pol II occupancy in both germline and somatic tissues of Drosophila. Nucleic acids research 1 40966519
2022 Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families. Genes 1 35328096
2014 Minimal detection of nuclear mutations in XP-V and normal cells treated with oxidative stress inducing agents. Journal of biochemical and molecular toxicology 1 25165004
2014 Site-directed Mutagenesis (Y52E) of POLH Affects Its Ability to Bypass Ultraviolet-induced DNA Lesions in HaCaT Cells. The West Indian medical journal 1 25429473
2003 [Establishment of a cell line with antisense-blocked POLH and the role of POLH in alkylating agent MNNG induced nontargeted mutagenesis]. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 1 14610738
2025 Four germline POLH variants, including two found in skin tumors, impair DNA polymerase η function and cellular tolerance to UV radiation and cisplatin. Chemico-biological interactions 0 40334807
2025 [Expression pattern of polyhedrin of BmNPV and involvement of importin α in the nuclear import of Polh]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 0 40769549
2025 Identification of radiation-sensitive genes as biomarkers for biodosimetry: an ex vivo analysis of TNFRSF10B, ZMAT3, POLH, and PLK2 in human blood samples. BMC medical genomics 0 41074151
2025 Germline variants of the POLH and RAD51 genes are candidate variants associated with risk of hormone receptor-negative young-onset breast cancer. NPJ breast cancer 0 41315479
2024 Identification of novel variants of XPA and POLH/XPV genes in xeroderma pigmentosum patients in Vietnam. Personalized medicine 0 39655645
2022 A new POLH mutation in a consanguineous Chinese family with xeroderma pigmentosum variant type. Clinical and experimental dermatology 0 35984432
2008 [Study on expression regularity of XPV mRNA in L-02 hepatic cells induced by hydroquinone]. Wei sheng yan jiu = Journal of hygiene research 0 19069642
2000 [Mutagenic analysis on the polyhedrin gene (polh) of Bombyx mori nuclear polyhedrosis virus (BmNPV)]. Yi chuan xue bao = Acta genetica Sinica 0 11209691

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