首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Polκ protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene
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Polκ protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene

机译:Polκ保护哺乳动物细胞免受苯并[a] py的致死和诱变作用

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摘要

Several low-fidelity DNA polymerases have recently been discovered that are able to bypass DNA lesions during DNA synthesis in vitro. The efficiency and accuracy of lesion bypass is, however, both polymerase and lesion specific. For example, in vitro studies revealed that human DNA polymerase κ (Polκ) is unable to insert a base opposite a cis-syn thymine-thymine dimer or cisplatin adduct, yet can bypass some DNA lesions such as abasic site and acetylaminofluorene-adducted guanine in an error-prone manner. More importantly, Polκ is able to bypass benzo[a]pyrene (B[a]P)-adducted guanine accurately and efficiently. To investigate the biological function of Polκ, we have generated mouse embryonic stem (ES) cells deficient in the Polk gene encoding the enzyme. Polk-deficient ES cells grow normally and their sensitivities to UV and x-ray radiation are only slightly affected. In contrast, the mutant cells are highly sensitive to both killing and mutagenesis induced by B[a]P. Furthermore, the spectrum of mutations recovered in the Polk-deficient cells is different from that in the wild-type cells. Thus, our results indicate that Polκ plays an important role in suppressing mutations at DNA lesions generated by B[a]P.
机译:最近发现了几种低保真DNA聚合酶,它们能够在体外DNA合成过程中绕过DNA损伤。然而,病变旁路的效率和准确性是聚合酶和病变特异性的。例如,体外研究表明,人类DNA聚合酶κ(Polκ)无法插入与顺式-胸腺嘧啶-胸腺嘧啶二聚体或顺铂加合物相反的碱基,但可以绕过DNA损伤,如脱碱基位点和乙酰氨基芴加成的鸟嘌呤。容易出错的方式。更重要的是,Polκ能够准确有效地绕过苯并[a] py(B [a] P)加成的鸟嘌呤。为了研究Polκ的生物学功能,我们已经生成了缺乏编码该酶的Polk基因的小鼠胚胎干(ES)细胞。缺乏猪肉的ES细胞正常生长,并且它们对UV和X射线辐射的敏感性仅受到轻微影响。相反,突变细胞对B [a] P诱导的杀伤和诱变均高度敏感。此外,在Polk缺陷细胞中回收的突变谱不同于野生型细胞。因此,我们的结果表明,Polκ在抑制B [a] P产生的DNA损伤处的突变中起重要作用。

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