title: Polycomb repressive complex 2 contributes to DNA double-strand break repair.
abstract: Polycomb protein histone methyltransferase, enhancer of Zeste homolog 2 (EZH2), is frequently overexpressed in human malignancy and is implicated in cancer cell proliferation and invasion. However, it is largely unknown whether EZH2 has a role in modulating the DNA damage response. Here, we show that polycomb repressive complex 2 (PRC2) is recruited to sites of DNA damage. This recruitment is independent of histone 2A variant X (H2AX) and the PI-3-related kinases ATM and DNA-PKcs. We establish that PARP activity is required for retaining PRC2 at sites of DNA damage. Furthermore, depletion of EZH2 in cells decreases the efficiency of DSB repair and increases sensitivity of cells to gamma-irradiation. These data unravel a crucial role of PRC2 in determining cancer cellular sensitivity following DNA damage and suggest that therapeutic targeting of EZH2 activity might serve as a strategy for improving conventional chemotherapy in a given malignancy.
authors.affiliation: Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
authors.forename: Stuart
authors.initials: S
authors.lastname: Campbell
authors.forename: Ismail Hassan
authors.initials: IH
authors.lastname: Ismail
authors.forename: Leah C
authors.initials: LC
authors.lastname: Young
authors.forename: Guy G
authors.initials: GG
authors.lastname: Poirier
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hendzel
mesh_terms: D047369:Chromatin Immunoprecipitation; D003114:Colony-Forming Units Assay; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D006801:Humans; D008856:Microscopy, Fluorescence; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism / Q000502:physiology*
chemical_list: C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: DNA damage; PARP; chromatin; epigenetics; polycomb group proteins
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