title: RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites.
abstract: In response to DNA damage, cells initiate complex signalling cascades leading to growth arrest and DNA repair. The recruitment of 53BP1 to damaged sites requires the activation of the ubiquitination cascade controlled by the E3 ubiquitin ligases RNF8 and RNF168, and methylation of histone H4 on lysine 20. However, molecular events that regulate the accessibility of methylated histones, to allow the recruitment of 53BP1 to DNA breaks, are unclear. Here, we show that like 53BP1, the JMJD2A (also known as KDM4A) tandem tudor domain binds dimethylated histone H4K20; however, JMJD2A is degraded by the proteasome following the DNA damage in an RNF8-dependent manner. We demonstrate that JMJD2A is ubiquitinated by RNF8 and RNF168. Moreover, ectopic expression of JMJD2A abrogates 53BP1 recruitment to DNA damage sites, indicating a role in antagonizing 53BP1 for methylated histone marks. The combined knockdown of JMJD2A and JMJD2B significantly rescued the ability of RNF8- and RNF168-deficient cells to form 53BP1 foci. We propose that the RNF8-dependent degradation of JMJD2A regulates DNA repair by controlling the recruitment of 53BP1 at DNA damage sites.
authors.affiliation: Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Sir Mortimer B. Davis Jewish General Hospital, Lady Davis Institute for Medical Research, Montréal, Québec, Canada.
authors.forename: Frédérick A
authors.initials: FA
authors.lastname: Mallette
authors.forename: Francesca
authors.initials: F
authors.lastname: Mattiroli
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Cui
authors.forename: Leah C
authors.initials: LC
authors.lastname: Young
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hendzel
authors.forename: Georges
authors.initials: G
authors.lastname: Mer
authors.forename: Titia K
authors.initials: TK
authors.lastname: Sixma
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D008969:Molecular Sequence Data; D011485:Protein Binding; D015398:Signal Transduction; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C486521:RNF8 protein, human; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D004247:DNA; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine