title: Germline mutations in BAP1 impair its function in DNA double-strand break repair.
abstract: The BRCA1-associated deubiquitylase BAP1 is mutated in several cancers, most notably mesothelioma and melanoma, where it is thought to promote oncogenesis. In this study, we present evidence that BAP1 functions as part of the DNA damage response (DDR). We found that BAP1 mediates rapid poly(ADP-ribose)-dependent recruitment of the polycomb deubiquitylase complex PR-DUB to sites of DNA damage. Furthermore, we identified BAP1 as a phosphorylation target for the DDR kinase ATM. Functionally, BAP1 promoted repair of DNA double-strand breaks, enhancing cell survival after DNA damage. Our results highlight the importance of ubiquitin turnover at sites of DNA damage, and they provide a mechanism to account for the tumor-suppressive function of BAP1.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt. iismail@ualberta.ca mhendzel@ualberta.ca.
authors.forename: Ismail Hassan
authors.initials: IH
authors.lastname: Ismail
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Riley
authors.initials: R
authors.lastname: Davidson
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu de Québec, Quebec City, Quebec, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gagné
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zhi Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu de Québec, Quebec City, Quebec, Canada.
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada. iismail@ualberta.ca mhendzel@ualberta.ca.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hendzel
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism
chemical_list: C400134:BAP1 protein, human; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase