SIRT1 Regulates UV-Induced DNA Repair through Deacetylating XPA
SIRT1 Regulates UV-Induced DNA Repair through Deacetylating XPA
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DOI：
10.1016/j.molcel.2010.07.006
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发表时间：
2010-07-30
期刊：
影响因子：
16
通讯作者：
Luo, Jianyuan
中科院分区：
文献类型：
--
作者：
Fan, Wei;Luo, Jianyuan
SIRT 1是一种依赖于NAD（+）的组蛋白去乙酰化酶，在基因转录、细胞代谢、应激反应和肿瘤发生等多种生物学过程中发挥着重要作用。着色性干皮病A组（XPA）是一个核心核苷酸切除修复（NER）过程中必不可少的因素。在这里，我们表明SIRT 1在NER通路的调节中起着重要的作用。SIRT 1的下调显著地使细胞对UV照射敏感。SIRT 1与XPA相互作用，并且在UV照射后相互作用增强。XPA可以在赖氨酸63和67处乙酰化。SIRT 1在体外和细胞中使XPA脱乙酰基。重要的是，SIRT 1介导的XPA脱乙酰化是最佳NER途径所必需的，因为与用野生型XPA补充的XPA细胞相比，用XPA-K6367 Q补充的XPA缺陷细胞（其模拟高度乙酰化的XPA）显示出显著更高的UV敏感性。此外，SIRT 1介导的XPA脱乙酰化增强了其与RPA 32的相互作用。我们的结果表明，SIRT 1通过调节XPA乙酰化状态来调节NER途径。
SIRT1, a NAD(+)-dependent histone deacetylase, plays crucial roles in multiple biological processes including gene transcription, cellular metabolism, stress response, and tumorigenesis. Xeroderma pigmentosum group A (XPA) is a core nucleotide excision repair (NER) factor essential for NER process. Here we show that SIRT1 plays an important role in the regulation of NER pathway. Downregulation of SIRT1 significantly sensitizes cells to UV irradiation. SIRT1 interacts with XPA, and the interaction is enhanced after UV irradiation. XPA can be acetylated at lysines 63 and 67. SIRT1 deacetylates XPA both in vitro and in cells. Importantly, SIRT1-mediated deacetylation of XPA is required for optimal NER pathway since XPA-deficient cells complemented with XPA-K6367Q, which mimics hyperacetylated XPA, display significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Furthermore, SIRT1-mediated XPA deacetylation enhances its interaction with RPA32. Our results demonstrate that SIRT1 regulates NER pathway through modulation of XPA acetylation status.