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USP 45 deubiquitylase controls ERCC 1– XPF endonuclease‐mediated DNA damage responses
Author(s) -
PerezOliva Ana B,
Lachaud Christophe,
Szyniarowski Piotr,
Muñoz Ivan,
Macartney Thomas,
Hickson Ian,
Rouse John,
Alessi Dario R
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201489184
Subject(s) - biology , endonuclease , dna , genetics
Reversible protein ubiquitylation plays important roles in various processes including DNA repair. Here, we identify the deubiquitylase USP 45 as a critical DNA repair regulator. USP 45 associates with ERCC 1, a subunit of the DNA repair endonuclease XPF – ERCC 1, via a short acidic motif outside of the USP 45 catalytic domain. Wild‐type USP 45, but not a USP 45 mutant defective in ERCC 1 binding, efficiently deubiquitylates ERCC 1 in vitro , and the levels of ubiquitylated ERCC 1 are markedly enhanced in USP 45 knockout cells. Cells lacking USP 45 are hypersensitive specifically to UV irradiation and DNA interstrand cross‐links, similar to cells lacking ERCC 1. Furthermore, the repair of UV ‐induced DNA damage is markedly reduced in USP 45‐deficient cells. ERCC 1 translocation to DNA damage‐induced subnuclear foci is markedly impaired in USP 45 knockout cells, possibly accounting for defective DNA repair. Finally, USP 45 localises to sites of DNA damage in a manner dependent on its deubiquitylase activity, but independent of its ability to bind ERCC 1– XPF . Together, these results establish USP 45 as a new regulator of XPF – ERCC 1 crucial for efficient DNA repair.