Academic Journal
ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer.
| Τίτλος: | ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer. |
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| Συγγραφείς: | Shi SN; 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., Xu Q; 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., Liao Z; 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., Gong W; 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., Cui Y; Department of Radiation Medicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China., Liu J; 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., Jiao X; 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., Wu Y; 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., Luo M; 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., Zhang Y; 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., Wang L; 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., Wen Y; 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., Pan W; 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., Zhao X; 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., Labrie M; Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada., Ding Z; Mills institute for Personalized Cancer Care, Fynn Biotechnologies Ltd., Jinan 250101, China., Mills GB; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States., Ma D; 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., Zhao GN; 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: zhaogn@tjh.tjmu.edu.cn., Gao Q; 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: qlgao@tjh.tjmu.edu.cn., Fang Y; 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: tongjify@163.com. |
| Πηγή: | Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2026 Jan; Vol. 84, pp. 101319. Date of Electronic Publication: 2025 Oct 28. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Churchill Livingstone Country of Publication: Scotland NLM ID: 9815369 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-2084 (Electronic) Linking ISSN: 13687646 NLM ISO Abbreviation: Drug Resist Updat Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Edinburgh ; Philadelphia : Churchill Livingstone, c1998- |
| Ιατρικοί όροι (MeSH): | Poly(ADP-ribose) Polymerase Inhibitors*/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors*/therapeutic use , Ovarian Neoplasms*/drug therapy , Ovarian Neoplasms*/genetics , Ovarian Neoplasms*/pathology , MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/antagonists & inhibitors , MRE11 Homologue Protein*/genetics, DNA Breaks, Double-Stranded/drug effects ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Recombinational DNA Repair/drug effects ; Female ; Humans ; Animals ; Mice ; Cell Line, Tumor ; Synthetic Lethal Mutations ; Xenograft Model Antitumor Assays ; Indazoles |
| Περίληψη: | 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. (Copyright © 2025 Elsevier Ltd. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interest GBM SAB/Consultant: AstraZeneca, BlueDot, Chrysallis Biotechnology, EllipsesPharma, ImmunoMET, Infinity, Ionis, Lilly, Medacorp, Nano-string, PDX Pharmaceuticals, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals; Stock/Options/Financial: Catena Pharmaceuticals, ImmunoMet, SignalChem, Tarveda. Turbine; Licensed Technology: HRD assay to Myriad Genetics, DSP patents with Nano-string. No disclosures were reported by the other authors. |
| Contributed Indexing: | Keywords: DNA damage response; Homologous recombination; Ovarian cancer; PARP inhibitor; ZBP1 |
| Substance Nomenclature: | 0 (Poly(ADP-ribose) Polymerase Inhibitors) EC 3.1.- (MRE11 Homologue Protein) 0 (MRE11 protein, human) HMC2H89N35 (niraparib) 0 (Piperidines) 0 (Indazoles) |
| Entry Date(s): | Date Created: 20251105 Date Completed: 20251209 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.drup.2025.101319 |
| PMID: | 41192279 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1532-2084 |
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| DOI: | 10.1016/j.drup.2025.101319 |