Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation
Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation
复制标题
TIP60 对 XPF 的乙酰化促进 XPF-ERCC1 复合物的组装和激活
DOI：
10.1038/s41467-020-14564-x
复制
发表时间：
2020-02-07
影响因子：
16.6
通讯作者：
Liu, Ting
中科院分区：
文献类型：
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作者：
Wang, Jiajia;He, Hanqing;Liu, Ting
XPF-ERCC1 异二聚体是一种结构特异性核酸内切酶，对于哺乳动物细胞中的核苷酸切除修复 (NER) 和链间交联 (ICL) 修复至关重要。然而，XPF 与 ERCC1 的结合是否以及如何受到调节尚未确定。在这里，我们表明，TIP60（也称为 KAT5）是一种单倍体不足的肿瘤抑制因子，在紫外线照射或丝裂霉素 C 处理后直接乙酰化 XPF 在 Lys911 处，并且这种乙酰化是 XPF-ERCC1 复合物组装和随后激活所必需的。从机制上讲，XPF 在 Lys911 处的乙酰化破坏了 Glu907-Lys911 盐桥，从而导致先前未识别的 ERCC1 第二个结合位点暴露。因此，XPF 乙酰化的丧失会损害损伤诱导的 XPF-ERCC1 相互作用，导致 NER 和 ICL 修复缺陷。我们的结果不仅揭示了调节XPF-ERCC1复合物组装和激活的机制，而且还为TIP60在维持基因组稳定性中的作用提供了重要的见解。
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 and that this acetylation is required for XPF-ERCC1 complex assembly and subsequent activation. Mechanistically, acetylation of XPF at Lys911 disrupts the Glu907-Lys911 salt bridge, thereby leading to exposure of a previously unidentified second binding site for ERCC1. Accordingly, loss of XPF acetylation impairs the damage-induced XPF-ERCC1 interaction, resulting in defects in both NER and ICL repair. Our results not only reveal a 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.