title: RETRACTED: Mitosis inhibits DNA double-strand break repair to guard against telomere fusions.
abstract: Mitotic cells inactivate DNA double-strand break (DSB) repair, but the rationale behind this suppression remains unknown. Here, we unravel how mitosis blocks DSB repair and determine the consequences of repair reactivation. Mitotic kinases phosphorylate the E3 ubiquitin ligase RNF8 and the nonhomologous end joining factor 53BP1 to inhibit their recruitment to DSB-flanking chromatin. Restoration of RNF8 and 53BP1 accumulation at mitotic DSB sites activates DNA repair but is, paradoxically, deleterious. Aberrantly controlled mitotic DSB repair leads to Aurora B kinase-dependent sister telomere fusions that produce dicentric chromosomes and aneuploidy, especially in the presence of exogenous genotoxic stress. We conclude that the capacity of mitotic DSB repair to destabilize the genome explains the necessity for its suppression during mitosis, principally due to the fusogenic potential of mitotic telomeres.
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Orthwein
authors.forename: Amélie
authors.initials: A
authors.lastname: Fradet-Turcotte
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Noordermeer
authors.forename: Marella D
authors.initials: MD
authors.lastname: Canny
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Brun
authors.forename: Jonathan
authors.initials: J
authors.lastname: Strecker
authors.forename: Cristina
authors.initials: C
authors.lastname: Escribano-Diaz
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D064107:Aurora Kinase B / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016615:Telomere / Q000235:genetics / Q000502:physiology*; D059505:Telomere Homeostasis / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C486521:RNF8 protein, human; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases; C576921:AURKB protein, human; D064107:Aurora Kinase B