Six Germline Genetic Variations Impair the Translesion Synthesis Activity of Human DNA Polymerase κ

Kim, Jaekwon; Yeom, Mina; Hong, Jin-Kyung; Song, Insil; Lee, Young‐Sam; Guengerich, F. Peter; Choi, Jeong‐Yun

doi:10.1021/acs.chemrestox.6b00244

Cited by 11 publications

(24 citation statements)

References 60 publications

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“…The same trend was observed with N 2 -CH 2 (9-anthracenyl)G, 8-oxoG, O 6 -methyl-G, or DNA containing an abasic site, except T44M had a decrease in activity opposite every lesion except 8-oxoG. 22…”

Section: Introductionsupporting

confidence: 67%

“…18,49–56 During the course of this work, several of these SNPs were added to cancer databases, and characterization of some of the variants mainly with DNA containing dG adducts was reported. 22,23 Here, we characterized the nine cancer-associated SNP variants of pol κ for their primer extension and mismatch extension activities on both preferred minor-groove DNA damage and nonpreferred major-groove DNA damage, determined overall stability, and characterized their dynamics with simulations.…”

Section: Resultsmentioning

confidence: 99%

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Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase κ

Antczak

Walker

Stern

et al. 2018

Chem. Res. Toxicol.

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Specialized DNA damage-bypass Y-family DNA polymerases contribute to cancer prevention by providing cellular tolerance to DNA damage that can lead to mutations and contribute to cancer progression by increasing genomic instability. Y-family polymerases can also bypass DNA adducts caused by chemotherapy agents. One of the four human Y-family DNA polymerases, DNA polymerase (pol) κ, has been shown to be specific for bypass of minor groove adducts and inhibited by major groove adducts. In addition, mutations in the gene encoding pol κ are associated with different types of cancers as well as with chemotherapy responses. We characterized nine variants of pol κ whose identity was inferred from cancer-associated single nucleotide polymorphisms for polymerization activity on undamaged and damaged DNA, their abilities to extend from mismatched or damaged base pairs at primer termini, and overall stability and dynamics. We find that these pol κ variants generally fall into three categories: similar activity to wild-type (WT) pol κ (L21F, I39T, P169T, F192C, and E292K), more active than WT pol κ (S423R), and less active than pol κ (R219I, R298H, and Y432S). Of these, only pol κ variants R298H and Y432S had markedly reduced thermal stability. Molecular dynamics (MD) simulations with undamaged DNA revealed that the active variant F192C and more active variant S423R with either correct or incorrect incoming nucleotide mimic WT pol κ with the correct incoming nucleotide, whereas the less active variants R219I, R298H, and Y432S with the correct incoming nucleotide mimic WT pol κ with the incorrect incoming nucleotide. Thus, the observations from MD simulations suggest a possible explanation for the observed experimental results that pol κ adopts specific active and inactive conformations that depend on both the protein variant and the identity of the DNA adduct.

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Section: Introductionsupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase κ

Antczak

Walker

Stern

et al. 2018

Chem. Res. Toxicol.

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“…To test this possibility, a carcinogenicity assay of repeated DSS treatment with Polk −/− mice is being conducted in our laboratories. In addition, there are several hypoactive Polκ variants in human population (Kim et al, ). It is worth examining whether these variants are sensitive to inflammation‐associated mutagenesis and carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase kappa counteracts inflammation‐induced mutagenesis in multiple organs of mice

Hakura

Sui

Sonoda

et al. 2019

Environ and Mol Mutagen

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In vitro studies indicate that DNA polymerase kappa (Polκ) is able to accurately and efficiently perform DNA synthesis using templates containing various types of DNA damage, including benzo[a]pyrene (BP)‐induced N2‐deoxyguanosine adducts. In this study, we examined sensitivity of inactivated Polk knock‐in (Polk−/−) mice to BP carcinogenicity in the colon by administering an oral dose of BP plus dextran sulfate sodium (DSS), an inflammation causing promoter of carcinogenesis. Although colon cancer was successfully induced by BP plus DSS, there was no significant difference in tumor incidence or multiplicity between Polk−/− and Polk+/+ mice. Malignant lymphoma was induced in thymus by the treatment only in Polk−/− mice, but it lacked statistical significance. Mutant frequencies (MFs) in the gpt reporter gene were strongly enhanced in colon; almost to the same extent in both types of mice. Micronucleus formation in bone marrow at the high dose of BP and DNA adducts in colon and lung was not significantly different between two types of mice. Surprisingly, however, Polk−/− mice exhibited significantly higher MFs in colon and lung than did Polk+/+ mice when they were treated with DSS alone. The most prominent mutation induced by DSS treatment was G:C to C:G transversion, whose specific MF in proximal colon was 30 times higher in Polk−/− than in Polk+/+ mice. DSS alone did not enhance MF at all in Polk+/+ mice. The results indicate that Polκ does not suppress BP‐induced mutagenesis and carcinogenesis in the colon, but counteracts inflammation‐induced mutagenesis in multiple organs. Environ. Mol. Mutagen. 60:320–330, 2019. © 2019 Wiley Periodicals, Inc.

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“…mismatch repair recognizes base-base mismatches induced by alkylating agents and eventually induce strand breaks in DNA via futile reactions (Karran and Bignami 1994). There are several human genetic variants of Polκ that have much lower catalytic activity in vitro (Kim et al 2016). If such lower catalytic activity is expressed in vivo, the human variants with lower catalytic activity of Polκ may be markedly sensitive to the clastogenic effects of endogenous H 2 O 2 compared to humans possessing higher catalytic activity of Polκ.…”

Section: Discussionmentioning

confidence: 99%

Effects of DNA polymerase kappa and mismatch repair on dose–responses of chromosome aberrations induced by three oxidative genotoxins in human cells

Nohmi

Matsumoto²

2019

Environ and Mol Mutagen

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Genotoxic carcinogens are regulated under the policy that there is no threshold or safe dose. It has been pointed out, however, that self-defense mechanisms, such as detoxification, DNA repair, and error-free translesion synthesis, may protect chromosome DNA from genotoxic insults, thereby constituting practical threshold. In this study, we examined dose responses of chromosome aberrations induced by three oxidative genotoxins, that is, hydrogen peroxide (H 2 O 2), menadione and paraquat, with or without DNA polymerase kappa (Polκ) activities and mismatch repair capacities in human cells. Polκ is involved in translesion synthesis across DNA damage and mismatch repair is responsible for correction of base-base mismatch in DNA. Polκ activity of the cells was inactivated either by point mutations in the catalytically essential amino acids (catalytically dead or CD) or by deletion of the POLK gene (knockout or KO). In the absence of mismatch repair, frequencies of chromosome aberrations induced by H 2 O 2 and menadione were not significantly different among CD, KO, and the wild type (WT) cells. In the presence of mismatch repair, however, cytotoxicity and clastogenicity were enhanced and Polκ modulated the sensitivity of the cells. No-observed-genotoxiceffect-levels (NOGELs) for H 2 O 2 and menadione were CD = KO < WT cells. In contrast, the sensitivities of the cells to paraquat were not significantly affected by the status of mismatch repair or Polκ activity. The results suggest that mismatch repair and Polκ coordinately modulate NOGELs for the clastogenicity of H 2 O 2 and menadione and also that DNA lesion(s) responsible for paraquat-induced chromosome aberrations are different from those induced by H 2 O 2 and menadione.

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Six Germline Genetic Variations Impair the Translesion Synthesis Activity of Human DNA Polymerase κ

Cited by 11 publications

References 60 publications

Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase κ

Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase κ

DNA polymerase kappa counteracts inflammation‐induced mutagenesis in multiple organs of mice

Effects of DNA polymerase kappa and mismatch repair on dose–responses of chromosome aberrations induced by three oxidative genotoxins in human cells

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