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 dysregulation in cancer cells is crucial for cancer development and therapies. Here, we report that enhancer of zeste homolog 2 (EZH2) directly methylates poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1), an essential enzyme involved in DNA repair, and regulates its activity. Functionally, EZH2-catalyzed methylation represses PARP1 catalytic activity, down-regulates the recruitment of x-ray repair cross-complementing group-1 to DNA lesions and its associated DNA damage repair; on the other hand, it protects the cells from nicotinamide adenine dinucleotide overconsumption upon DNA damage formation. Meanwhile, EZH2-mediated methylation regulates PARP1 transcriptional and oncogenic activity, at least in part, through impairing PARP1-E2F1 interaction and E2F1 transcription factor activity. EZH2 and PARP1 inhibitors synergistically suppress prostate cancer growth. Collectively, our findings uncover an insight of EZH2 functions in fine-tuning PARP1 activity during DNA damage repair and cancer progression, which provides a rationale for combinational targeting EZH2 and PARP1 in cancer.
Authors
- Qiaqia Li (ORCID: https://orcid.org/0000-0002-5052-3331)
- Weihua Jiang (ORCID: https://orcid.org/0000-0002-0918-7946)
- Kaifu Chen (ORCID: https://orcid.org/0000-0003-1009-4357)
- Yi Yang (ORCID: https://orcid.org/0000-0002-1958-7249)
- Quan Wang (ORCID: https://orcid.org/0000-0001-9199-0190)
- Dongyu Zhao (ORCID: https://orcid.org/0000-0003-3882-0218)
- Hengyao Niu (ORCID: https://orcid.org/0000-0003-1768-0674)
- Qi Cao (ORCID: https://orcid.org/0000-0002-5140-3681)
- Sundeep Kalantry (ORCID: https://orcid.org/0000-0003-0763-8050)
- Xiaotong Lu (ORCID: https://orcid.org/0000-0002-5395-9384)
- Qingshu Meng (ORCID: https://orcid.org/0000-0001-8093-7482)
- Yanan Ren (ORCID: https://orcid.org/0000-0001-9586-3690)
- Rendong Yang (ORCID: https://orcid.org/0000-0002-9512-2240)
- Jonathan C. Trinidad (ORCID: https://orcid.org/0000-0002-8279-1509)
- Ting-You Wang (ORCID: https://orcid.org/0000-0003-4354-3198)
- Chaehyun Yum
- Yongyong Yang (ORCID: https://orcid.org/0000-0003-2297-5848)
- Rui Wang (ORCID: https://orcid.org/0000-0003-2782-7772)
- Yixiang Zhang (ORCID: https://orcid.org/0000-0003-3422-8436)
- Yanqiang Li (ORCID: https://orcid.org/0000-0001-6846-6884)
- Clair Harris (ORCID: https://orcid.org/0000-0003-3609-7417)
- Jiangchuan Shen (ORCID: https://orcid.org/0000-0003-1699-564X)
- Qi Liu (ORCID: https://orcid.org/0000-0002-7652-4201)
Institutions
- Northwestern University (US)
- Boston Children's Hospital (US)
- Houston Methodist (US)
- University of Minnesota (US)
- Harvard University (US)
- University of Michigan (US)
- Indiana University Bloomington (US)
- Rocky Mountain Research (United States) (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1126/sciadv.adl2804
- Citations
- 11
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 3.11
Funders
- Northwestern University
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- National Cancer Institute