USP45 deubiquitylase controls ERCC1-XPF endonuclease-mediated DNA damage responses

Ana B. Perez-Oliva (Lead / Corresponding author), Christophe Lachaud, Piotr Szyniarowski, Ivan Muñoz, Thomas Macartney, Ian Hickson, John Rouse (Lead / Corresponding author), Dario R. Alessi (Lead / Corresponding author)

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    24 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)326-343
    Number of pages18
    JournalEMBO Journal
    Volume34
    Issue number3
    DOIs
    Publication statusPublished - 3 Feb 2015

    Keywords

    • interstrand cross-link
    • nucleotide excision repair
    • ubiquitin
    • UV irradiation

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