[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-336211-105":59,"doc-detail-336211-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","parp-inhibitors-suppress-tumours-via-centrosome-error-induced-senescence-independent-of-dna-damage-response","PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage response","","Poly(ADP-ribose) polymerase (PARP) inhibitors are clinically used against BRCA1/2-associated tumours via synthetic lethality, yet survival benefits have been reported beyond homologous recombination deficiency, requiring an explanation of PARP inhibitor mechanisms beyond DNA damage repair. Using CRISPR knock-in BRCA1 mutant cancer cells, biochemical and cell biological assays assessed PARP inhibitor effects, with xenograft and PDX models validating in vivo tumour suppression. Mechanistic data reveal centrosome error-driven senescence as an alternative therapeutic pathway.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/parp-inhibitors-suppress-tumours-via-centrosome-error-induced-senescence-independent-of-dna-damage-response/336211/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/parp-inhibitors-suppress-tumours-via-centrosome-error-induced-senescence-independent-of-dna-damage-response/336211.png","ImageObject",300,407,{"name":92,"@type":93},"Emma Wilson","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",16,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What therapeutic mechanism is proposed for PARP inhibitors beyond DNA damage repair?","Question",{"text":113,"@type":114},"PARP inhibitors suppress tumours by triggering centrosome error-induced senescence independent of the DNA damage response, mediated through transient extra spindle poles and PAR synthesized at mitotic centrosomes.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How were BRCA1 mutant cancer cells generated and evaluated in this study?",{"text":118,"@type":114},"A CRISPR-based knock-in approach established stable BRCA1 mutant cancer cells, whose responses to PARP inhibitors were tested using biochemical and cell biological experiments.",{"name":120,"@type":111,"acceptedAnswer":121},"What role does PAR synthesized by PARP2 (not PARP1) play during mitosis?",{"text":122,"@type":114},"At mitotic centrosomes, PARP2 synthesizes PAR that clusters transient extra spindle poles, helping prevent mitotic error; PARP inhibitors disrupt PAR production and abrogate correction of the extra-pole error, leading to senescence.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},336211,1790079740,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":26},3848291630094,"https://eur-avatar.wpscdn.com/davatar_085a072bc5b1113ac321206ff7593b45","Articles   \nPARP inhibitors suppress tumours via centrosome errorinduced senescence independent of DNA damage response  \nWei Yue,a,b,c,d,i Xinyu Li,a,b,c,d,i Xiaolu Zhan,e,i Lei Wang,f,g Jihong Ma,a,b,c,d Meiyu Bi,a,b,c,d Qilong Wang,a,b,c,d Xiaoyang Gu,a,b,c,d Bingteng Xie,h Tong Liu,e Hongyan Guo,b,c,d Xin Zhu,a,b,c,d Chen Song,f,g Jie Qiao,a,b,c,d and Mo Lia,b,c,d,∗  \naState Key Laboratory of Female Fertility Promotion, Centre for Reproductive Medicine, Department of Obstetrics and Gynaecology, Peking University Third Hospital, Beijing, 100191, China  \nbNational Clinical Research Centre for Obstetrics and Gynaecology (Peking University Third Hospital), Beijing, 100191, China cKey Laboratory of Assisted Reproduction (Peking University), Ministry of Education, Beijing 100191, China  \ndBeijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China eDepartment of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China  \nfCentre for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China gPeking-Tsinghua Centre for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China  \nhKey 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  \nSummary  \nBackground 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.  \nMethods 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.  \nFindings 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.  \nInterpretation 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.  \nFunding 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) .  \nCopyright © 2024 The Author(s) . Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).  \nKeywords: Poly(ADP-ribose); PARP inhibitor; BRCA1; Mitosis; Spindle pole; Tumours  \nIntroduction  \nAs an essential homologous recombination (HR) factor, BRCA1 functions in the maintenance of genome  \nstability.1 Mutations of BRCA1 are known to confer a high lifetime risk of breast and ovarian cancers in women.2,3 The advent of poly (ADP-ribose) polymerase  \n*Corresponding aut","cbCaidg6RnJdNow6","https://ap.wps.com/l/cbCaidg6RnJdNow6","pdf",6230705,24,"English","# Summary\n## Background\n## Methods\n## Findings\n## Interpretation\n# Research in context\n## Evidence before this study\n## Added value of this study\n## Implications of all the available evidence","[{\"question\":\"What therapeutic mechanism is proposed for PARP inhibitors beyond DNA damage repair?\",\"answer\":\"PARP inhibitors suppress tumours by triggering centrosome error-induced senescence independent of the DNA damage response, mediated through transient extra spindle poles and PAR synthesized at mitotic centrosomes.\"},{\"question\":\"How were BRCA1 mutant cancer cells generated and evaluated in this study?\",\"answer\":\"A CRISPR-based knock-in approach established stable BRCA1 mutant cancer cells, whose responses to PARP inhibitors were tested using biochemical and cell biological experiments.\"},{\"question\":\"What role does PAR synthesized by PARP2 (not PARP1) play during mitosis?\",\"answer\":\"At mitotic centrosomes, PARP2 synthesizes PAR that clusters transient extra spindle poles, helping prevent mitotic error; PARP inhibitors disrupt PAR production and abrogate correction of the extra-pole error, leading to senescence.\"}]","PARP inhibitors suppress tumours via centrosome error-induced senescence independent of DNA damage response | PDF",1790014135]