title: Polycomb group proteins in the DNA damage response: a link between radiation resistance and "stemness".
abstract: Polycomb group proteins, which have well-established roles in gene regulation, were recently found to accumulate on chromatin surrounding DNA damage and to contribute up to 40 percent of the radiation resistance of cell lines. The oncogenic polycomb protein, BMI-1, was additionally shown to be essential for the increased radiation resistance observed in stem cells and cancer stem cells relative to their more differentiated counterparts. BMI-1, is a very early DNA damage response protein that accumulates through a γH2AX/RNF8-independent, but poly(ADP-ribosyl)ation-dependent mechanism at DNA double-strand breaks. BMI-1 acts together with RING2 and other components of the PRC1 histone H2A E3 ubiquitin ligase to ubiquitylate histones H2A and H2AX in response to DNA damage. BMI-1 dependent ubiquitin modifications are at the base of an ubiquitin pathway that enhances radioresistance through the accumulation of RAP80, 53BP1, and BRCA1. Members of the PRC2 histone H3 lysine 27 methyltransferase complex are also recruited to sites of DSBs but it remains to be determined whether the histone methyltransferase and histone E3 ubiquitin ligase polycomb complexes function in concert or independently during DNA repair. Understanding the contribution of polycomb group proteins to the DNA damage response may lead to novel therapeutic strategies that increase the response of human cancers to therapies that work through DNA damage, while simultaneously sensitizing the cancer stem cell population that would otherwise lead to relapse.
authors.affiliation: Cross Cancer Institute and Department of Oncology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Gieni
authors.forename: Ismail H
authors.initials: IH
authors.lastname: Ismail
authors.forename: Stuart
authors.initials: S
authors.lastname: Campbell
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hendzel
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins; D020868:Gene Silencing; D056488:Histone Chaperones; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C400134:BAP1 protein, human; C069077:BMI1 protein, human; D019313:BRCA1 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C466234:UIMC1 protein, human; D025801:Ubiquitin; D063150:Polycomb Repressive Complex 1; D043222:Ubiquitin Thiolesterase