EZH2 directly methylates PARP1 and regulates its activity in cancer
DNA repair dysregulation is a key driver of cancer development. Understanding the molecular mechanisms underlying DNA repair pathways and their dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly (ADP-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, at lysine 607 and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, inhibits the recruitment of X-ray repair cross-complementing group-1 (XRCC1) recruitment to DNA lesions and hence impairs DNA damage repair. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. Collectively, our findings uncover a novel insight of EZH2 functions in DNA damage repair and cancer progression, which provides a new rationale for combinational targeting EZH2 and PARP1 in cancer. Overall design: Comparative gene expression profiling analysis of RNA-seq data for PARP1-KD C4-2 cells stably expressing PAPR1-WT or -K607A.