PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage responseResearch in context
Wei Yue,
Xinyu Li,
Xiaolu Zhan,
Lei Wang,
Jihong Ma,
Meiyu Bi,
Qilong Wang,
Xiaoyang Gu,
Bingteng Xie,
Tong Liu,
Hongyan Guo,
Xin Zhu,
Chen Song,
Jie Qiao,
Mo Li
Affiliations
Wei Yue
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Xinyu Li
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Xiaolu Zhan
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
Lei Wang
Centre for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China; Peking-Tsinghua Centre for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
Jihong Ma
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Meiyu Bi
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Qilong Wang
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Xiaoyang Gu
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Bingteng Xie
Key Laboratory of Molecular Medicine and Biological Diagnosis and Treatment (Ministry of Industry and Information Technology), School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
Tong Liu
Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China
Hongyan Guo
National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Xin Zhu
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Chen Song
Centre for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China; Peking-Tsinghua Centre for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China
Jie Qiao
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
Mo Li
State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China; National Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China; Key Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China; Corresponding author. State Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China.
Summary: Background: Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as promising chemotherapeutic drugs primarily against BRCA1/2-associated tumours, known as synthetic lethality. However, recent clinical trials reported patients’ survival benefits from PARP inhibitor treatments, irrelevant to homologous recombination deficiency. Therefore, revealing the therapeutic mechanism of PARP inhibitors beyond DNA damage repair is urgently needed, which can facilitate precision medicine. Methods: A CRISPR-based knock-in technology was used to establish stable BRCA1 mutant cancer cells. The effects of PARP inhibitors on BRCA1 mutant cancer cells were evaluated by biochemical and cell biological experiments. Finally, we validated its in vivo effects in xenograft and patient-derived xenograft (PDX) tumour mice. Findings: In this study, we uncovered that the majority of clinical BRCA1 mutations in breast cancers were in and near the middle of the gene, rather than in essential regions for DNA damage repair. Representative mutations such as R1085I and E1222Q caused transient extra spindle poles during mitosis in cancer cells. PAR, which is synthesized by PARP2 but not PARP1 at mitotic centrosomes, clustered these transient extra poles, independent of DNA damage response. Common PARP inhibitors could effectively suppress PARP2-synthesized PAR and induce cell senescence by abrogating the correction of mitotic extra-pole error. Interpretation: Our findings uncover an alternative mechanism by which PARP inhibitors efficiently suppress tumours, thereby pointing to a potential new therapeutic strategy for centrosome error-related tumours. Funding: Funded by National Natural Science Foundation of China (NSFC) (T2225006, 82272948, 82103106), Beijing Municipal Natural Science Foundation (Key program Z220011), and the National Clinical Key Specialty Construction Program, P. R. China (2023).
