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

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.

• Authors: Jiajia Wang, Hanqing He, Binbin Chen, Guixing Jiang, Liping Cao, Haiping Jiang, Guofei Zhang, Jianxiang Chen, Jun Huang, Bing Yang, Chun Zhou, Ting Liu
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 786 (02 07 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32034146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Multiprotein Complexes
• xeroderma pigmentosum group F protein
• Mitomycin
• KAT5 protein, human
• Lysine Acetyltransferase 5
• ERCC1 protein, human
• Endonucleases
• SIRT1 protein, human
• Sirtuin 1
• Lysine

Topics

• Acetylation
• Binding Sites
• DNA Damage
• DNA Repair (drug effects, physiology, radiation effects)
• DNA-Binding Proteins (genetics, metabolism)
• Endonucleases (genetics, metabolism)
• HEK293 Cells
• HeLa Cells
• Humans
• Lysine (metabolism)
• Lysine Acetyltransferase 5 (genetics, metabolism)
• Mitomycin (pharmacology)
• Multiprotein Complexes
• Sirtuin 1 (metabolism)
• Ultraviolet Rays