title: CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage.
abstract: Polycomb group (PcG) proteins are involved in epigenetic silencing where they function as major determinants of cell identity, stem cell pluripotency and the epigenetic gene silencing involved in cancer development. Recently numerous PcG proteins, including CBX4, have been shown to accumulate at sites of DNA damage. However, it remains unclear whether or not CBX4 or its E3 sumo ligase activity is directly involved in the DNA damage response (DDR). Here we define a novel role for CBX4 as an early DDR protein that mediates SUMO conjugation at sites of DNA lesions. DNA damage stimulates sumoylation of BMI1 by CBX4 at lysine 88, which is required for the accumulation of BMI1 at DNA damage sites. Moreover, we establish that CBX4 recruitment to the sites of laser micro-irradiation-induced DNA damage requires PARP activity but does not require H2AX, RNF8, BMI1 nor PI-3-related kinases. The importance of CBX4 in the DDR was confirmed by the depletion of CBX4, which resulted in decreased cellular resistance to ionizing radiation. Our results reveal a direct role for CBX4 in the DDR pathway.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada.
authors.forename: Ismail Hassan
authors.initials: IH
authors.lastname: Ismail
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Gagné
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Caron
authors.forename: Darin
authors.initials: D
authors.lastname: McDonald
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Xu
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hendzel
mesh_terms: D000818:Animals; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D057809:HEK293 Cells; D006801:Humans; D008025:Ligases; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases
chemical_list: C069077:BMI1 protein, human; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D050828:Protein Inhibitors of Activated STAT; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; D008025:Ligases; C570427:CBX4 protein, human; D008239:Lysine