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.

Keywords: :

• PARP
• DNA damage
• polycomb group proteins
• chromatin
• epigenetics

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The Alberta Cancer Foundation (to MH) and the Canadian Institute of Health Research (CIHR) (to GP and MJH); an Alberta Innovates Health Solutions (AIHS) Senior Scholar (to MJH); Alberta Cancer Foundation postdoctoral fellowships (to IHI) and Alberta Cancer Foundation graduate student scholarship (to SC). We thank Drs Andre Nussenzweig, Mien-Chie Hung, and Xiaochun Yu for providing valuable reagents. We also thank the Cellular Imaging Facility at the Cross Cancer Institute for the use of microscopes and image analysis software.