2. Academic Validation
  3. ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer

ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer

  • Drug Resist Updat. 2026 Jan:84:101319. doi: 10.1016/j.drup.2025.101319.
Shen-Nan Shi 1,  Qiuyang Xu 1,  Zhiqi Liao 1,  Wenjian Gong 1,  Yilin Cui 2,  Jiahao Liu 1,  Xiaofei Jiao 1,  Yijie Wu 1,  Mengshi Luo 1,  Yuewen Zhang 1,  Linghui Wang 1,  Yuanjia Wen 1,  Wen Pan 1,  Xuejiao Zhao 3,  Marilyne Labrie 4,  Zhiyong Ding 5,  Gordon B Mills 6,  Ding Ma 1,  Guang-Nian Zhao 7,  Qinglei Gao 8,  Yong Fang 9
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 3 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States.
  • 4 Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada.
  • 5 Mills institute for Personalized Cancer Care, Fynn Biotechnologies Ltd., Jinan 250101, China.
  • 6 Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States.
  • 7 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 8 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 9 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
PMID: 41192279 DOI: 10.1016/j.drup.2025.101319
Abstract

ZBP1, a classic pattern recognition receptor (PRR), has been implicated in regulating programmed cell death and the innate immune response. However, the role of ZBP1 in the nucleus remains largely undefined. Here, we found that nuclear ZBP1 localizes to the site of DNA double-stranded breaks (DSBs) following DNA damage and impairs homologous recombination (HR) repair through its interaction with MRE11. ZBP1 interacts with MRE11 through RHIM A and B domains and inhibits the enzymatic activity of MRE11, ultimately leading to the suppression of HR and DNA damage repair (DDR). These processes are initiated via ATM-mediated ZBP1 phosphorylation at S106. Consistent with these findings, in vitro and in vivo models both exhibit increased sensitivity to PARP Inhibitor treatment following ZBP1 overexpression. Furthermore, in our neoadjuvant niraparib monotherapy study (NCT05407841) higher ZBP1 expression correlates with better response to PARP inhibition and prolonged PFS in high-grade serous ovarian Cancer (HGSOC). This study describes a novel function of ZBP1 for regulating HR, which confers synthetic lethality to PARP inhibition in ovarian Cancer. ZBP1 thus serves as a potential therapy target and biomarker of response to PARP inhibitors and potentially Other therapeutic agents such as platin analogs that are synthetically lethal with defective HR.

Keywords

DNA damage response; Homologous recombination; Ovarian cancer; PARP inhibitor; ZBP1.

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