title: An E2-guided E3 Screen Identifies the RNF17-UBE2U Pair as Regulator of the Radiosensitivity, Immunodeficiency, Dysmorphic Features, and Learning Difficulties (RIDDLE) Syndrome Protein RNF168.
abstract: Protein ubiquitination has emerged as a pivotal regulatory reaction that promotes cellular responses to DNA damage. With a goal to delineate the DNA damage signal transduction cascade, we systematically analyzed the human E2 ubiquitin- and ubiquitin-like-conjugating enzymes for their ability to mobilize the DNA damage marker 53BP1 onto ionizing radiation-induced DNA double strand breaks. An RNAi-based screen identified UBE2U as a candidate regulator of chromatin responses at double strand breaks. Further mining of the UBE2U interactome uncovered its cognate E3 RNF17 as a novel factor that, via the radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties (RIDDLE) syndrome protein RNF168, enforces DNA damage responses. Our screen allowed us to uncover new players in the mammalian DNA damage response and highlights the instrumental roles of ubiquitin machineries in promoting cell responses to genotoxic stress.
authors.affiliation: From the School of Biomedical Sciences, Li Ka Shing Faculty of Medicine and.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: From the School of Biomedical Sciences, Li Ka Shing Faculty of Medicine and.
authors.forename: Liwei
authors.initials: L
authors.lastname: An
authors.affiliation: From the School of Biomedical Sciences, Li Ka Shing Faculty of Medicine and.
authors.forename: Hoi-Man
authors.initials: HM
authors.lastname: Ng
authors.affiliation: From the School of Biomedical Sciences, Li Ka Shing Faculty of Medicine and mhsy@hku.hk.
authors.forename: Shirley M H
authors.initials: SM
authors.lastname: Sy
authors.affiliation: From the School of Biomedical Sciences, Li Ka Shing Faculty of Medicine and huen.michael@hku.hk.|the State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Michael S Y
authors.initials: MS
authors.lastname: Huen
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D006367:HeLa Cells; D006801:Humans; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002843:Chromatin; C498301:TP53BP1 protein, human; D014157:Transcription Factors; D000071857:Tumor Suppressor p53-Binding Protein 1; D025801:Ubiquitin; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DNA damage response; E3 ubiquitin ligase; RNA interference (RNAi); small interfering RNA (siRNA); ubiquitin; ubiquitin-conjugating enzyme (E2 enzyme)