Acetylation of XPF by TIP60 facilitates XPF-ERCC1 complex assembly and activation

Jiajia Wang, Hanqing He, Binbin Chen, Guixing Jiang, Liping Cao, Haiping Jiang, Guofei Zhang, Jianxiang Chen, Jun Huang, Bing Yang, Chun Zhou and Ting Liu ()
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Jiajia Wang: Zhejiang University School of Medicine
Hanqing He: Zhejiang University
Binbin Chen: Zhejiang University School of Medicine
Guixing Jiang: Zhejiang University School of Medicine
Liping Cao: Zhejiang University School of Medicine
Haiping Jiang: Zhejiang University School of Medicine
Guofei Zhang: Zhejiang University School of Medicine
Jianxiang Chen: Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital
Jun Huang: Zhejiang University
Bing Yang: Zhejiang University
Chun Zhou: Zhejiang University School of Medicine
Ting Liu: Zhejiang University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14564-x

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