Affinage

POLK

DNA polymerase kappa · UniProt Q9UBT6

Length
870 aa
Mass
98.8 kDa
Annotated
2026-06-10
45 papers in source corpus 12 papers cited in narrative 12 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

POLK encodes DNA polymerase kappa, a low-fidelity translesion synthesis (TLS) polymerase that replicates DNA across naturally occurring lesions and thereby suppresses spontaneous mutagenesis in vivo (PMID:11006276, PMID:19783230). The enzyme copies even undamaged templates with high single-base substitution and deletion error rates, exhibits unusual error specificity favoring T·CMP mispairs and non-reiterated insertions/deletions, retains moderate processivity (a property contributed by its C-terminal zinc-cluster region), and lacks any 3'→5' proofreading exonuclease activity (PMID:11006276). Its lesion-bypass capacity is selective: pol kappa cannot replicate past a cis-syn thymine-thymine dimer, a (6-4) photoproduct, an abasic site, or a cisplatin adduct, but it carries out limited, potentially mutagenic bypass of 2-acetylaminofluorene adducts and is a proficient extender of mispaired and lesion-associated primer termini, implicating it in a two-polymerase mode of mutagenic bypass (PMID:10760255, PMID:11024016, PMID:11842189). Genetic ablation in mice produces a tissue-restricted spontaneous mutator phenotype dominated by G:C base-pair changes, and a catalytic-dead knock-in in chicken DT40 cells phenocopies the knockout for methyl methanesulfonate sensitivity, establishing that the catalytic activity itself is required for tolerance of monoalkylation damage (PMID:19783230, PMID:19166845). POLK transcription is directly repressed by wild-type p53 acting through its promoter (PMID:15202001), and somatic catalytic-core missense mutations found in prostate cancer reduce bypass efficiency and elevate misincorporation, linking POLK function to genome stability in disease (PMID:26046662).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2000 High

    Established the basic enzymatic identity of pol kappa as an error-prone, non-proofreading DNA polymerase, defining the fidelity and lesion-bypass constraints that frame its biological role.

    Evidence In vitro fidelity, processivity, and lesion-bypass assays with purified recombinant human protein

    PMID:10760255 PMID:11006276

    Open questions at the time
    • Did not identify the physiological lesions it bypasses in cells
    • Structural basis of error specificity and zinc-cluster contribution to processivity not resolved
  2. 2001 High

    Refined the lesion-bypass specificity, showing pol kappa is blocked at cisplatin adducts but performs limited mutagenic bypass of AAF and is not stimulated by PCNA in vitro.

    Evidence Template-directed polymerase and lesion-bypass assays with purified GST-fusion protein, inhibitor sensitivity testing

    PMID:11024016

    Open questions at the time
    • In vitro lack of PCNA stimulation does not establish cofactor requirements in cells
    • Range of bypassable adducts incompletely mapped
  3. 2002 High

    Identified pol kappa as a promiscuous mispair extender capable of extending past T-T dimer-associated mispairs, positioning it in a two-polymerase mutagenic bypass mechanism.

    Evidence In vitro primer extension on defined mismatch and lesion substrates with purified protein

    PMID:11842189

    Open questions at the time
    • Partner inserter polymerase in cells not defined
    • Cellular context of two-polymerase bypass not demonstrated
  4. 2004 Medium

    Connected POLK to the DNA damage response by showing its promoter is directly repressed by wild-type p53, linking TLS capacity to tumor suppressor control.

    Evidence Promoter-reporter assays with DNA-binding-deficient p53 control and comparison across p53 genotype MEFs

    PMID:15202001

    Open questions at the time
    • Direct p53 occupancy at the endogenous promoter not shown
    • Physiological consequence of derepression not measured
  5. 2009 High

    Demonstrated the in vivo requirement for pol kappa catalytic activity, showing knockout mice are spontaneous mutators (G:C-biased) and that catalytic-dead pol kappa phenocopies knockout for alkylation sensitivity.

    Evidence Polk knockout mouse with cII reporter mutation assay; catalytic-dead knock-in in DT40 cells with MMS sensitivity epistasis

    PMID:19166845 PMID:19783230

    Open questions at the time
    • Specific endogenous adducts bypassed in each tissue not identified
    • Tissue restriction of the mutator phenotype mechanistically unexplained
  6. 2015 High

    Linked POLK catalytic function to human disease by showing cancer-associated catalytic-core mutations impair bypass and elevate misincorporation.

    Evidence Site-directed mutagenesis of prostate-cancer variants with in vitro TLS and fidelity assays

    PMID:26046662

    Open questions at the time
    • Causal role of these variants in tumorigenesis not established
    • Cellular phenotype of the mutants not tested
  7. 2024 Medium

    Revealed regulation and localization dynamics of pol kappa: activity-dependent and age-dependent nuclear/cytoplasmic redistribution in neurons, and post-transcriptional stabilization by PTBP2 coupled to MRN/ATM-CHK2 signaling.

    Evidence Longitudinal immunofluorescence and co-localization in brain tissue; PTBP2-KO CML cells with rescue, Co-IP, comet, γH2AX, and SCE assays (PTBP2 study is a preprint)

    PMID:39026788 PMID:42126963

    Open questions at the time
    • PTBP2-MRE11 axis rests on a single-lab preprint with Co-IP lacking reciprocal validation
    • Functional meaning of cytoplasmic pol kappa accumulation unknown
    • Mechanism coupling neuronal activity to nuclear pol kappa levels unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological recruitment, regulation, and full repertoire of endogenous lesions handled by pol kappa in vivo remain incompletely defined.
  • No structural model of pol kappa engaging its native substrates in the timeline
  • Mechanism linking p53 repression and PTBP2 stabilization to cellular damage tolerance not integrated
  • Identity of inserter polymerases partnering pol kappa in cellular bypass unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140097 catalytic activity, acting on DNA 5 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 3
Partners
MRE11PTBP2

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Human POLK-encoded DNA polymerase kappa (pol kappa) copies undamaged DNA with high error rates (average single-base substitution ~7×10⁻³ and deletion ~2×10⁻³), has unusual error specificity (high proportion of T·CMP mispairs and extraordinary rates of non-reiterated nucleotide deletions/additions), and possesses moderate processivity (chains of ≥25 nucleotides), with the C-terminal region (containing two zinc clusters) contributing to processivity. Pol kappa lacks detectable 3'→5' proofreading exonuclease activity. In vitro DNA polymerase fidelity assays, processivity assays, biochemical characterization of purified recombinant protein The Journal of biological chemistry High 11006276
2000 Human POLK-encoded protein (named Pol theta by authors, now established as pol kappa) is a DNA polymerase that cannot bypass a cis-syn thymine-thymine dimer, a (6-4) photoproduct, or an abasic site. It misincorporates deoxynucleotides on non-damaged DNA templates with frequency ~10⁻³ to 10⁻⁴. Purification of hDINB1-encoded protein, in vitro DNA polymerase assay, steady-state kinetic analysis, lesion bypass assay Proceedings of the National Academy of Sciences of the United States of America High 10760255
2001 Human pol kappa (POLK product) is a template-directed DNA polymerase that lacks detectable 3'→5' proofreading exonuclease activity, is not stimulated by PCNA in vitro, requires Mg²⁺ or Mn²⁺ as metal cofactor (Mg²⁺ preferred), is insensitive to aphidicolin and dideoxynucleotides, cannot bypass a cisplatin adduct, but shows limited bypass of a 2-acetylaminofluorene (AAF) lesion incorporating dCTP or dTTP (potentially mutagenic). GST-fusion protein expressed in insect cells, purified and tested in template-directed polymerase assay, lesion bypass assay, inhibitor sensitivity assays The Journal of biological chemistry High 11024016
2002 Human POLK-encoded pol kappa is a promiscuous extender of primer-terminal mispairs on non-damaged DNA templates. It is also efficient at extending from a G opposite the 3'T of a cis-syn T-T dimer, implicating it in mutagenic bypass of T-T dimers via a two-polymerase mechanism. In its mismatch extension ability, pol kappa resembles pol zeta more than the phylogenetically related pol eta or pol iota. In vitro primer extension assay with purified pol kappa on templates with defined mismatches and lesions Proceedings of the National Academy of Sciences of the United States of America High 11842189
1999 Transient expression of mouse Dinb1 (POLK ortholog) cDNA in cultured mouse cells resulted in a ~10-fold increase in point mutations, with ~30% frameshift mutations, demonstrating that the POLK/Dinb1 product can promote mutagenesis in mammalian cells. Transient transfection of mammalian cells, mutation frequency assay Genes to cells : devoted to molecular & cellular mechanisms Medium 10620008
2004 Wild-type p53, but not a DNA-binding-deficient mutant p53 (R273H), strongly inhibits POLK promoter activity in human lung cancer cell lines. POLK promoter activity is significantly higher in p53⁻/⁻ MEFs than in p53⁺/⁻ or p53⁺/⁺ MEFs, establishing p53 as a direct transcriptional repressor of POLK. Promoter-reporter assay, transcription start site mapping, comparison of p53⁻/⁻ vs p53⁺/⁺ MEFs International journal of oncology Medium 15202001
2009 Polk⁻/⁻ mice exhibit a spontaneous mutator phenotype with significantly increased mutation frequencies in kidney, liver, and lung (but not spleen or testis), with mutation spectra dominated by G:C base pair changes. This establishes Pol kappa as required for accurate translesion synthesis past naturally occurring DNA adducts in vivo. Polk knockout mouse model, lambda-phage cII reporter transgene mutation frequency assay across tissues DNA repair High 19783230
2009 Introduction of a polymerase-dead point mutation into chicken POLK (in DT40 cells) phenocopies POLK knockout in sensitivity to methyl methanesulfonate (MMS), demonstrating that the catalytic polymerase activity of Pol kappa is required for repair of monoalkylation damage. The polymerase-dead Pol kappa does not interfere with other polymerases. Targeted knock-in of catalytic-dead mutation in chicken DT40 cells, MMS sensitivity assay, comparison with POLK⁻/⁻ double knockout FEBS letters Medium 19166845
2005 Mouse Polkappa/human POLK gene produces multiple alternatively spliced transcripts specifically in testis (11 forms in mouse, 5 forms in human identified by RT-PCR), a phenomenon not shared by several other TLS polymerases, suggesting POLK may encode multiple Pol kappa isoforms in testis. RT-PCR amplification of coding sequence from testis cDNA DNA repair Low 15661663
2015 Somatic missense mutations in the catalytic core of POLK identified in prostate cancer (p.E29K, p.G154E, p.F155S, p.E430K, p.L442F) significantly diminish catalytic efficiency for lesion bypass (AP site) and increase misincorporation of T, C, and G compared to wild-type, functionally implicating these residues in TLS activity. Site-directed mutagenesis, bacterial expression and purification of POLK variants, in vitro TLS assay, nucleotide incorporation fidelity assay Human mutation High 26046662
2024 POLK is highly expressed in mouse neurons. With chronological aging, there is a progressive reduction of nuclear POLK and concomitant accumulation in the cytoplasm. Nuclear POLK colocalizes with DNA damage sites and DNA repair proteins. Cytoplasmic POLK accumulates with stress granules and endo/lysosomal markers. Neuronal activity increases nuclear POLK levels and reduces the cytoplasmic fraction. Nuclear POLK is higher in GABAergic interneurons than excitatory pyramidal neurons. Immunofluorescence, longitudinal imaging, co-localization with DNA damage and repair markers, neuronal activity manipulation, subcellular fractionation-equivalent imaging in brain tissue eLife Medium 39026788 42126963
2024 PTBP2 (an RNA-binding protein) stabilizes POLK mRNA via its 3'UTR, promoting increased Pol kappa protein production. PTBP2 knockout in CML cells increases DNA damage (comet assay, γH2AX foci), and overexpression of Pol kappa in PTBP2-KO cells restores normal phenotype. POLK interacts with MRE11 of the MRN complex, thereby governing ATM-CHK2 activation. Elevated PTBP2/Pol kappa promotes sister chromatid exchange and genomic instability. PTBP2 knockout CML cells, Pol kappa overexpression rescue, co-immunoprecipitation (POLK-MRE11 interaction), comet assay, γH2AX foci, SCE assay, BrdU incorporation bioRxivpreprint Low

Source papers

Stage 0 corpus · 45 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Multiple pathways for SOS-induced mutagenesis in Escherichia coli: an overexpression of dinB/dinP results in strongly enhancing mutagenesis in the absence of any exogenous treatment to damage DNA. Proceedings of the National Academy of Sciences of the United States of America 288 9391106
2000 Fidelity and processivity of DNA synthesis by DNA polymerase kappa, the product of the human DINB1 gene. The Journal of biological chemistry 214 11006276
2000 The human DINB1 gene encodes the DNA polymerase Poltheta. Proceedings of the National Academy of Sciences of the United States of America 164 10760255
2002 Human DINB1-encoded DNA polymerase kappa is a promiscuous extender of mispaired primer termini. Proceedings of the National Academy of Sciences of the United States of America 140 11842189
1999 Mutation enhancement by DINB1, a mammalian homologue of the Escherichia coli mutagenesis protein dinB. Genes to cells : devoted to molecular & cellular mechanisms 138 10620008
2001 Purification and characterization of pol kappa, a DNA polymerase encoded by the human DINB1 gene. The Journal of biological chemistry 110 11024016
1995 dinP, a new gene in Escherichia coli, whose product shows similarities to UmuC and its homologues. Mutation research 62 7596361
2009 Polk mutant mice have a spontaneous mutator phenotype. DNA repair 51 19783230
2016 Migration of DEHP and DINP into dust from PVC flooring products at different surface temperature. The Science of the total environment 46 26824397
1999 Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalate (MEHP) and diisononylphthalate (DINP): a comparison of rat and human hepatocytes in vitro. Archives of toxicology 36 10650916
2004 Elevated expression of DNA polymerase kappa in human lung cancer is associated with p53 inactivation: Negative regulation of POLK promoter activity by p53. International journal of oncology 33 15202001
2018 DINP aggravates autoimmune thyroid disease through activation of the Akt/mTOR pathway and suppression of autophagy in Wistar rats. Environmental pollution (Barking, Essex : 1987) 30 30447474
2017 TRPA1 mediated aggravation of allergic contact dermatitis induced by DINP and regulated by NF-κB activation. Scientific reports 28 28240277
2012 A dose response study to assess effects after dietary administration of diisononyl phthalate (DINP) in gestation and lactation on male rat sexual development. Reproductive toxicology (Elmsford, N.Y.) 28 22944045
2000 Comparative in vivo hepatic effects of Di-isononyl phthalate (DINP) and related C7-C11 dialkyl phthalates on gap junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX), and DNA synthesis in rat and mouse liver. Toxicological sciences : an official journal of the Society of Toxicology 28 10774813
2019 Promoting differentiation and lipid metabolism are the primary effects for DINP exposure on 3T3-L1 preadipocytes. Environmental pollution (Barking, Essex : 1987) 27 31546122
2019 Inhibitions of HMGB1 and TLR4 alleviate DINP-induced asthma in mice. Toxicology research 25 31588340
2009 Effects of maternal exposure to di-isononylphthalate (DINP) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) on steroidogenesis in the fetal rat testis and adrenal gland. Reproductive toxicology (Elmsford, N.Y.) 22 19490997
2019 In vitro cytotoxic effects of secondary metabolites of DEHP and its alternative plasticizers DINCH and DINP on a L929 cell line. International journal of hygiene and environmental health 21 30898526
2018 Exposure to a combination of formaldehyde and DINP aggravated asthma-like pathology through oxidative stress and NF-κB activation. Toxicology 21 29758289
2015 Somatic Mutations in Catalytic Core of POLK Reported in Prostate Cancer Alter Translesion DNA Synthesis. Human mutation 18 26046662
2014 Association of POLK polymorphisms with platinum-based chemotherapy response and severe toxicity in non-small cell lung cancer patients. Cell biochemistry and biophysics 18 24948471
2022 Distinctive roles of translesion polymerases DinB1 and DnaE2 in diversification of the mycobacterial genome through substitution and frameshift mutagenesis. Nature communications 17 35918328
1999 Effects of di-isononyl phthalate (DINP) on peroxisomal markers in the marmoset-DINP is not a peroxisome proliferator. The Journal of toxicological sciences 17 10478338
2023 Mediation of endoplasmic reticulum stress and NF-κB signaling pathway in DINP-exacerbated allergic asthma: A toxicological study with Balb/c mice. Journal of hazardous materials 15 37657325
2023 Biologically relevant reductions in fetal testosterone and Insl3 induced by in utero exposure to high levels of di-isononyl phthalate (DINP) in male rats. Toxicology and applied pharmacology 13 36921846
2020 Systematic comparison of the male reproductive tract in fetal and adult Wistar rats exposed to DBP and DINP in utero during the masculinisation programming window. Toxicology letters 12 33086118
2022 Effects of DEHP, DEHT and DINP Alone or in a Mixture on Cell Viability and Mitochondrial Metabolism of Endothelial Cells In Vitro. Toxics 11 35878278
2018 Effect of Gestational and Lactational Exposure to DEHP, DINP, and DEP on Intestinal Morphology, Disaccharidases, and Alkaline Phosphatase in Rats during Postnatal Development. American journal of perinatology 11 29715699
2021 Effects of Di-Isononyl Phthalate (DiNP) on Follicular Atresia in Zebrafish Ovary. Frontiers in endocrinology 10 34194395
2005 Multiple PolK (POLK) transcripts in mammalian testis. DNA repair 10 15661663
2023 The IL-31/TRPV1 pathway mediates allergic asthma exacerbated by DINP dermal exposure in OVA-sensitized Balb/c mice. The Science of the total environment 8 38154627
2005 Infection and organ failure in the surgical patient: a tribute to seminal contributions by Hiram C. Polk, Jr, M.D. American journal of surgery 8 16023425
2023 DEHP and DINP accelerate aging effects in male and female of Drosophila melanogaster depend on AKT/FOXO pathway. Toxicology in vitro : an international journal published in association with BIBRA 6 38016509
2022 Isolation of DiNP-Degrading Microbes from the Mouse Colon and the Influence DiNP Exposure Has on the Microbiota, Intestinal Integrity, and Immune Status of the Colon. Toxics 6 35202261
2024 Thyroid and neurobehavioral effects of DiNP on GH3 cells and larval zebrafish (Danio rerio). Chemosphere 5 38866335
2023 DDIT4 is essential for DINP-induced autophagy of ovarian granulosa cells. Ecotoxicology and environmental safety 4 37976928
2024 Are the new phthalates safe? Evaluation of Diisononilphtalate (DINP) effects in porcine ovarian cell cultures. Environmental toxicology and pharmacology 3 38331371
2009 Introduction and characterization of a polymerase-dead point mutation into the POLK gene in vertebrates. FEBS letters 2 19166845
1993 Fort Polk Heart Smart Program. Part III: Assessment of dietary intake of military wives. Military medicine 1 8502394
2026 Effects of prenatal DINP exposure induced hepatic steatosis and underlying mechanism. Toxicology and applied pharmacology 0 41490809
2026 Acute exposure to diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) impacts pituitary hormones and inflammatory markers, suggesting altered reproductive aging in adult female mice. Toxicological sciences : an official journal of the Society of Toxicology 0 41712757
2026 An altered cell-specific subcellular distribution of translesion synthesis DNA polymerase kappa (POLK) in aging mouse neurons. eLife 0 42126963
2025 Integrated in silico and GC-MS analysis of Momordica charantia Linn. phytocomponents against DiNP phthalate and B[a]P toxicity: A focus on amyloid beta protein and acetylcholinesterase in neurodegenerative disease. Computational biology and chemistry 0 40450790
2024 An altered cell-specific subcellular distribution of translesion synthesis DNA polymerase kappa (POLK) in aging neurons. bioRxiv : the preprint server for biology 0 39026788

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