TY - JOUR
T1 - The polycomb group protein EZH2 impairs DNA repair in breast epithelial cells
AU - Zeidler, Michael
AU - Varambally, Sooryanarayana
AU - Cao, Qi
AU - Chinnaiyan, Arul M.
AU - Ferguson, David O.
AU - Merajver, Sofia D.
AU - Kleer, Celina G.
N1 - Funding Information:
Abbreviations: HR, homologous recombination; DSB, double-strand break; PcG, Polycomb group proteins Address all correspondence to: Celina G. Kleer, MD, Department of Pathology, University of Michigan Medical School, 3510C MSRB1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0605. E-mail: [email protected] 1This work was supported, in part, by National Institutes of Health grants R01CA107469 (C.G.K.), CA090876-K08 (C.G.K.), and R01CA77612 (A.M.C.); Army grants DAMD17-02-1-0490 and DAMD17-02-1-491 (C.G.K.); the Burroughs Wellcome Research Fund (S.D.M.); and the Breast Cancer Research Foundation (S.D.M). Received 18 July 2005; Revised 26 August 2005; Accepted 29 August 2005.
PY - 2005/11
Y1 - 2005/11
N2 - The Polycomb group protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.
AB - The Polycomb group protein EZH2 is a transcriptional repressor involved in controlling cellular memory and has been linked to aggressive and metastatic breast cancer. Here we report that EZH2 decreased the expression of five RAD51 paralog proteins involved in homologous recombination (HR) repair of DNA double-strand breaks (RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, and XRCC3), but did not affect the levels of DMC1, a gene that only functions in meiosis. EZH2 overexpression impaired the formation of RAD51 repair foci at sites of DNA breaks. Overexpression of EZH2 resulted in decreased cell survival and clonogenic capacity following DNA damage induced independently by etoposide and ionizing radiation. We suggest that EZH2 may contribute to breast tumorigenesis by specific downregulation of RAD51-like proteins and by impairment of HR repair. We provide mechanistic insights into the function of EZH2 in mammalian cells and uncover a link between EZH2, a regulator of homeotic gene expression, and HR DNA repair. Our study paves the way for exploring the blockade of EZH2 overexpression as a novel approach for the prevention and treatment of breast cancer.
KW - Breast cancer
KW - DNA repair
KW - EZH2
KW - Homologous recombination
KW - RAD51 paralogs
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U2 - 10.1593/neo.05472
DO - 10.1593/neo.05472
M3 - Article
C2 - 16331887
AN - SCOPUS:33644826522
SN - 1522-8002
VL - 7
SP - 1011
EP - 1019
JO - Neoplasia
JF - Neoplasia
IS - 11
ER -