XPF蛋白的乙酰化修饰在DNA损伤修复中的功能与作用机制研究

XPF-ERCC1核酸内切酶复合物在NER(Nucleotide Excision Repair)和ICL(Interstrand Crosslink)修复中起着至关重要的作用。但是，XPF-ERCC1复合物是如何被组装和激活的还很不清楚。我们发现乙酰转移酶TIP60能够通过与XPF的直接相互作用进而催化XPF K911位点的乙酰化，并且该位点的乙酰化能够特异的被UV irradiation和mitomycin C所诱导。通过进一步分析XPF-ERCC1的NMR结构，我们发现XPF K911位点的乙酰化可能会破坏E907-K911盐桥的形成并暴露出XPF与ERCC1一个新的相互作用位点，进而促进XPF-ERCC1复合物的完全组装与激活。通过该项目的实施，我们不仅可以阐明XPF-ERCC1复合物在细胞内组装和激活的分子机制，还可以进一步揭示肿瘤抑制因子TIP60在基因组稳定性维持中的作用。

The XPF-ERCC1 heterodimer is a structure-specific endonuclease that is essential for nucleotide excision repair (NER) and interstrand crosslink (ICL) repair in mammalian cells. However, whether and how XPF binding to ERCC1 is regulated has not yet been established. Here, we show that TIP60 (also known as KAT5), a haplo-insufficient tumor suppressor, directly acetylates XPF at Lys911 following UV irradiation or treatment with mitomycin C. Loss of XPF acetylation causes defects in both NER and ICL repair. Mechanistically, acetylation of XPF at Lys911 may disrupt the Glu907-Lys911 salt bridge, thereby leading to exposure of a previously unidentified second binding site for ERCC1. Our results not only reveal a novel mechanism that regulates XPF-ERCC1 complex assembly and activation, but also provide important insight into the role of TIP60 in the maintenance of genome stability.