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 (H2 O2 ), 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 H2 O2 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-genotoxic-effect-levels (NOGELs) for H2 O2 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 H2 O2 and menadione and also that DNA lesion(s) responsible for paraquat-induced chromosome aberrations are different from those induced by H2 O2 and menadione. Environ. Mol. Mutagen. 61:193-199, 2020. © 2019 Wiley Periodicals, Inc.

中文翻译：

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DNA聚合酶kappa和错配修复对人类细胞中三种氧化遗传毒素诱导的染色体畸变的剂量反应的影响。

没有阈值或安全剂量的政策规定了对遗传毒性致癌物的管理。然而，已经指出，诸如排毒，DNA修复和无错转录合成等自卫机制可以保护染色体DNA免受遗传毒性损害，从而构成实用的阈值。在这项研究中，我们研究了由三种氧化遗传毒素（过氧化氢（H2 O2），甲萘醌和百草枯）诱导的染色体畸变的剂量响应，无论是否存在DNA聚合酶kappa（Polκ）活性和人细胞错配修复能力。Polκ参与跨DNA损伤的跨病变合成，错配修复负责纠正DNA中的碱基错配。细胞的Polκ活性通过催化必需氨基酸的点突变（催化死亡或CD）或通过删除POLK基因（敲除或KO）而失活。在没有错配修复的情况下，H2 O2和甲萘醌诱导的染色体畸变频率在CD，KO和野生型（WT）细胞之间没有显着差异。但是，在存在错配修复的情况下，细胞毒性和杀伤力增强，Polκ调节细胞的敏感性。H2O2和甲萘醌的未观察到的遗传毒性作用水平（NOGEL）为CD = KO <WT细胞。相反，错配修复或Polκ活性的状态对百草枯细胞的敏感性没有显着影响。结果表明，错配修复和Polκ协同调节NOGEL对H2 O2和甲萘醌的致突变性，并且负责百草枯诱导的染色体畸变的DNA损伤与H2 O2和甲萘醌诱导的染色体畸变不同。环境。大声笑 诱变剂。61：193-199，2020.©2019 Wiley Periodicals，Inc.