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Here, we identify the deubiquitylase USP45 as a critical DNA repair regulator. USP45 associates with ERCC1, a subunit of the DNA repair endonuclease XPF\u2013ERCC1, via a short acidic motif outside of the USP45 catalytic domain. Wild\u2010type USP45, but not a USP45 mutant defective in ERCC1 binding, efficiently deubiquitylates ERCC1\n                    <jats:italic>in vitro<\/jats:italic>\n                    , 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\u2010links, similar to cells lacking ERCC1. Furthermore, the repair of UV\u2010induced DNA damage is markedly reduced in USP45\u2010deficient cells. ERCC1 translocation to DNA damage\u2010induced 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\u2013XPF. Together, these results establish USP45 as a new regulator of XPF\u2013ERCC1 crucial for efficient DNA repair.\n                  <\/jats:p>","DOI":"10.15252\/embj.201489184","type":"journal-article","created":{"date-parts":[[2014,12,23]],"date-time":"2014-12-23T22:26:27Z","timestamp":1419373587000},"page":"326-343","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["USP45 deubiquitylase controls ERCC1\u2013XPF endonuclease\u2010mediated DNA damage responses"],"prefix":"10.1038","volume":"34","author":[{"given":"Ana B","family":"Perez\u2010Oliva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Lachaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Szyniarowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Macartney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Hickson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Rouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario R","family":"Alessi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,12,23]]},"reference":[{"key":"BFEMBJ201489184_CR1","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.cell.2013.08.029","volume":"155","author":"S Adam","year":"2013","unstructured":"Adam S, Polo SE, Almouzni G (2013) Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA. 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