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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Human Dna Polymerase η Activity And Translocation Is Regulated By Phosphorylation
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Human Dna Polymerase η Activity And Translocation Is Regulated By Phosphorylation

机译：人DNA聚合酶η的活性和易位受磷酸化作用

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摘要

Human DNA polymerase η (pol η) can replicate across UV-induced pyrimidine dimers, and defects in the gene encoding pol η result in a syndrome called xeroderma pigmentosum variant (XP-V). XP-V patients are prone to the development of cancer in sun-exposed areas, and cells derived from XP-V patients demonstrate increased sensitivity to UV radiation and a higher mutation rate compared with wild-type cells, pol η has been shown to replicate across a wide spectrum of DNA lesions introduced by environmental or chemotherapeutic agents, or during nucleotide starvation, suggesting that the biological roles for pol η are not limited to repair of UV-damaged DNA. The high error rate of pol η requires that its intracellular activity be tightly regulated. Here, we show that the phosphorylation of pol η increased after UV irradiation, and that treatment with caffeine, siRNA against ATR, or an inhibitor of PKC (calphostin C), reduced the accumulation of pol 17 at stalled replication forks after UV irradiation or treatment with cisplatin and gemcitabine. Site-specific mutagenesis (S587A and T617A) of pol η at two putative PKC phosphorylation sites located in the protein-protein interaction domain prevented nuclear foci formation induced by UV irradiation or treatment with gemcitabine/cisplatin. In addition, XP-V cell lines stably expressing either the S587A or T617A mutant form of pol η were more sensitive to UV radiation and gemcitabine/cisplatin than control cells expressing wild-type pol η. These results suggest that phosphorylation is one mechanism by which the cellular activity of pol η is regulated.
机译：人类DNA聚合酶η（polη）可以在紫外线诱导的嘧啶二聚体上复制，编码polη的基因缺陷会导致一种称为干性色素变性（XP-V）的综合症。 XP-V患者倾向于在阳光暴晒的地方发展癌症，并且与野生型细胞相比，XP-V患者衍生的细胞对紫外线辐射的敏感性更高，突变率更高，已证明polη可复制在环境或化学治疗剂或核苷酸饥饿期间引入的广泛DNA损伤中，提示polη的生物学作用不仅限于修复紫外线损伤的DNA。 polη的高错误率要求严格调节其细胞内活性。在这里，我们表明，紫外线辐射后polη的磷酸化增加，并且咖啡因，针对ATR的siRNA或PKC抑制剂（钙磷蛋白C）的处理减少了紫外线辐射或处理后停滞的复制叉中pol 17的积累。与顺铂和吉西他滨。位于蛋白质-蛋白质相互作用域中两个推定的PKC磷酸化位点上的polη的位点特异性诱变（S587A和T617A）阻止了紫外线照射或吉西他滨/顺铂治疗诱导的核灶形成。此外，稳定表达polη的S587A或T617A突变体形式的XP-V细胞系比表达野生型polη的对照细胞对UV辐射和吉西他滨/顺铂更敏感。这些结果表明，磷酸化是调节polη的细胞活性的一种机制。

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