Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Mol Cell. 2010 Jul 30;39(2):247-58. doi: 10.1016/j.molcel.2010.07.006.
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.
SIRT1 是一种依赖 NAD(+)的组蛋白去乙酰化酶，在多种生物学过程中发挥着关键作用，包括基因转录、细胞代谢、应激反应和肿瘤发生。 Xeroderma pigmentosum 组 A (XPA) 是核苷酸切除修复 (NER) 过程中必不可少的核心因子。在这里，我们表明 SIRT1 在调节 NER 途径中起着重要作用。SIRT1 的下调显著增加了细胞对 UV 照射的敏感性。SIRT1 与 XPA 相互作用，并且这种相互作用在 UV 照射后增强。XPA 可以在赖氨酸 63 和 67 处被乙酰化。SIRT1 在体外和细胞内均可使 XPA 去乙酰化。重要的是，SIRT1 介导的 XPA 去乙酰化对于最佳 NER 途径是必需的，因为与野生型 XPA 互补的 XPA 缺陷细胞与用 XPA-K6367Q （模拟高度乙酰化的 XPA）互补的细胞相比，显示出明显更高的 UV 敏感性。此外，SIRT1 介导的 XPA 去乙酰化增强了其与 RPA32 的相互作用。我们的结果表明，SIRT1 通过调节 XPA 乙酰化状态来调节 NER 途径。
