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Lookup NU author(s): Professor Ian HicksonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Reversible protein ubiquitylation plays important roles in various processes including DNA repair. Here, we identify the deubiquitylase USP45 as a critical DNA repair regulator. USP45 associates with ERCC1, a subunit of the DNA repair endonuclease XPF–ERCC1, via a short acidic motif outside of the USP45 catalytic domain. Wild‐type USP45, but not a USP45 mutant defective in ERCC1 binding, efficiently deubiquitylates ERCC1 in vitro, and the levels of ubiquitylated ERCC1 are markedly enhanced in USP45 knockout cells. Cells lacking USP45 are hypersensitive specifically to UV irradiation and DNA interstrand cross‐links, similar to cells lacking ERCC1. Furthermore, the repair of UV‐induced DNA damage is markedly reduced in USP45‐deficient cells. ERCC1 translocation to DNA damage‐induced subnuclear foci is markedly impaired in USP45 knockout cells, possibly accounting for defective DNA repair. Finally, USP45 localises to sites of DNA damage in a manner dependent on its deubiquitylase activity, but independent of its ability to bind ERCC1–XPF. Together, these results establish USP45 as a new regulator of XPF–ERCC1 crucial for efficient DNA repair.
Author(s): Perez-Oliva AB, Lachaud C, Szyniarowski P, Muñoz I, Macartney T, Hickson I, Rouse J, Alessi DR
Publication type: Article
Publication status: Published
Journal: The EMBO Journal
Online publication date: 23/12/2014
Acceptance date: 21/11/2014
Date deposited: 05/01/2017
ISSN (electronic): 1460-2075
PubMed id: 25538220
Notes: A search for interactors of the ubiquitin‐specific protease USP45, whose gene is frequently deleted in certain cancers, reveals that reversible ubiquitylation regulates ERCC1–XPF, a key endonuclease of DNA nucleotide excision repair and interstrand cross‐link repair, and protects cells from UV damage.
USP45 deubiquitylase binds to the ERCC1 endonuclease and catalyses its deubiquitylation.
Cells lacking USP45 are hypersensitive to UV irradiation and DNA interstrand cross‐links, similar to cells lacking ERCC1.
A mutant of USP45 that does not bind ERCC1 is incapable of rescuing DNA damage sensitivity of USP45‐deficient cells.
USP45 rapidly and transiently localises to sites of DNA damage.
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