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Excision repair is required for genotoxin-induced mutagenesis in mammalian cells

机译:基因毒素诱导的哺乳动物细胞诱变需要切除修复

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摘要

Certain hexavalent chromium [Cr(VI)] compounds are human lung carcinogens. Although much is known about Cr-induced DNA damage, very little is known about mechanisms of Cr(VI) mutagenesis and the role that DNA repair plays in this process. Our goal was to investigate the role of excision repair (ER) pathways in Cr(VI)-mediated mutagenesis in mammalian cells. Repair-proficient Chinese hamster ovary cells (AA8), nucleotide excision repair (NER)-deficient (UV-5) and base excision repair (BER)-inhibited cells were treated with Cr(VI) and monitored for forward mutation frequency at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus. BER was inhibited using methoxyamine hydrochloride (Mx), which binds to apurinic/apyrimidinic sites generated during BER. Notably, we found that both NER-deficient (UV-5 and UV-41) and BER-inhibited (AA8 + Mx) cells displayed attenuated Cr(VI) mutagenesis. To determine whether this was unique to Cr(VI), we included the alkylating agent, methylmethane sulfonate (MMS) and ultraviolet (UV) radiation (260 nm) in our studies. Similar to Cr(VI), UV-5 cells exhibited a marked attenuation of MMS mutagenesis, but were hypermutagenic following UV exposure. Moreover, UV-5 cells expressing human xeroderma pigmentosum complementation group D displayed similar sensitivity to Cr(VI) and MMS-induced mutagenesis as AA8 controls, indicating that the genetic loss of NER was responsible for attenuated mutagenesis. Interestingly, Cr(VI)-induced clastogenesis was also attenuated in NER-deficient and BER-inhibited cells. Taken together, our results suggest that NER and BER are required for Cr(VI) and MMS-induced genomic instability. We postulate that, in the absence of ER, DNA damage is channeled into an error-free system of DNA repair or damage tolerance.
机译:某些六价铬[Cr(VI)]化合物是人肺致癌物。尽管对Cr引起的DNA损伤知之甚少,但对Cr(VI)诱变的机理及其在此过程中DNA修复所起的作用知之甚少。我们的目标是研究切除修复(ER)通路在Cr(VI)介导的哺乳动物细胞诱变中的作用。用Cr(VI)处理具有修复能力的中国仓鼠卵巢细胞(AA8),缺乏核苷酸切除修复(NER)的(UV-5)和抑制碱基切除修复(BER)的细胞,并在次黄嘌呤中监测其正向突变频率-鸟嘌呤磷酸核糖基转移酶(HPRT)基因座。使用盐酸甲氧基胺(Mx)抑制BER,该盐结合到BER期间产生的嘌呤/嘧啶位上。值得注意的是,我们发现NER缺陷(UV-5和UV-41)细胞和BER抑制(AA8 + Mx)细胞均显示出Cr(VI)诱变减弱。为了确定这是否是六价铬所独有的,我们在研究中包括了烷基化剂,甲基甲烷磺酸盐(MMS)和紫外线(UV)辐射(260 nm)。与Cr(VI)相似,UV-5细胞显示出MMS诱变的显着减弱,但在暴露于UV后具有高致突变性。此外,表达人类干皮色素补充组D的UV-5细胞对Cr(VI)和MMS诱导的诱变表现出与AA8对照相似的敏感性,表明NER的遗传损失是减毒诱变的原因。有趣的是,Cr(VI)诱导的分裂发生在NER缺陷和BER抑制的细胞中也减弱了。两者合计,我们的结果表明NER和BER是Cr(VI)和MMS诱导的基因组不稳定性所必需的。我们假设,在没有ER的情况下,DNA损伤被引导到DNA修复或损伤耐受性的无错系统中。

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