title: Systematic characterization of deubiquitylating enzymes for roles in maintaining genome integrity.
abstract: DNA double-strand breaks (DSBs) are perhaps the most toxic of all DNA lesions, with defects in the DNA-damage response to DSBs being associated with various human diseases. Although it is known that DSB repair pathways are tightly regulated by ubiquitylation, we do not yet have a comprehensive understanding of how deubiquitylating enzymes (DUBs) function in DSB responses. Here, by carrying out a multidimensional screening strategy for human DUBs, we identify several with hitherto unknown links to DSB repair, the G2/M DNA-damage checkpoint and genome-integrity maintenance. Phylogenetic analyses reveal functional clustering within certain DUB subgroups, suggesting evolutionally conserved functions and/or related modes of action. Furthermore, we establish that the DUB UCHL5 regulates DSB resection and repair by homologous recombination through protecting its interactor, NFRKB, from degradation. Collectively, our findings extend the list of DUBs promoting the maintenance of genome integrity, and highlight their potential as therapeutic targets for cancer.
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nishi
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Wijnhoven
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: le Sage
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Jorrit
authors.initials: J
authors.lastname: Tjeertes
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Galanty
authors.affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
authors.forename: Josep V
authors.initials: JV
authors.lastname: Forment
authors.affiliation: Cellular &Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clague
authors.affiliation: Cellular &Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Urbé
authors.affiliation: 1] The Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK [2] The Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Jackson
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004798:Enzymes / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000145:classification / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D010802:Phylogeny; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D004798:Enzymes; D007527:Isoenzymes; C072725:NFRKB protein, human; D049452:Green Fluorescent Proteins; C421245:UCHL5 protein, human; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex