Zeidler Michael, Varambally Sooryanarayana, Cao Qi, Chinnaiyan Arul M, Ferguson David O, Merajver Sofia D, Kleer Celina G
Department of Pathology, University of Michigan, Arbor, MI, USA.
Neoplasia. 2005 Nov;7(11):1011-9. doi: 10.1593/neo.05472.
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.
多梳蛋白家族成员EZH2是一种参与调控细胞记忆的转录抑制因子，并且与侵袭性和转移性乳腺癌相关。在此我们报告，EZH2降低了参与DNA双链断裂同源重组（HR）修复的5种RAD51旁系蛋白（RAD51B/RAD51L1、RAD51C/RAD51L2、RAD51D/RAD51L3、XRCC2和XRCC3）的表达，但不影响仅在减数分裂中起作用的基因DMC1的水平。EZH2的过表达损害了DNA断裂位点处RAD51修复灶的形成。EZH2过表达导致依托泊苷和电离辐射独立诱导的DNA损伤后细胞存活率和克隆形成能力降低。我们认为，EZH2可能通过特异性下调RAD51样蛋白以及损害HR修复而促进乳腺肿瘤发生。我们提供了关于EZH2在哺乳动物细胞中功能的机制性见解，并揭示了同源异型基因表达调节因子EZH2与HR DNA修复之间的联系。我们的研究为探索阻断EZH2过表达作为预防和治疗乳腺癌的新方法铺平了道路。
