The Polycomb group protein EZH2 impairs DNA repair in breast epithelial cells.
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.
Zeidler
Michael
M
Department of Pathology, University of Michigan, Arbor, MI, USA.
Varambally
Sooryanarayana
S
Cao
Qi
Q
Chinnaiyan
Arul M
AM
Ferguson
David O
DO
Merajver
Sofia D
SD
Kleer
Celina G
CG
D001940:Breast / Q000166:cytology*; D002453:Cell Cycle / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D004249:DNA Damage; D017931:DNA Primers; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008677:Metaphase; D063151:Polycomb Repressive Complex 2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2