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The molecular functions of PARP inhibition in thyroid cancers remain insufficiently defined. This study shows niraparib drives DNA damage accumulation while promoting PAR-dependent Pol II pausing, suppressing DIMT1 transcription and causing global translation inhibition. It also activates NF-κB signaling by reducing p65 PARylation, lowering ubiquitination and degradation via RNF146. Bortezomib further potentiates niraparib anti-tumor efficacy in vitro and in vivo, supporting mechanistic rationale for BRCA-mutant–independent cancer cells.",{"@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-inhibitor-shuts-down-the-global-translation-of-thyroid-cancer-through-promoting-pol-ii-binding-to-dimt1-pause/380290/",{"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-inhibitor-shuts-down-the-global-translation-of-thyroid-cancer-through-promoting-pol-ii-binding-to-dimt1-pause/380290.png","ImageObject",300,407,{"name":92,"@type":93},"Taylor Morgan","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does niraparib play in thyroid cancer cells?","Question",{"text":113,"@type":114},"Niraparib promotes DNA damage accumulation and suppresses DIMT1 transcription by inducing PAR-dependent Pol II pausing, which leads to global translation inhibition in thyroid cancer cells.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does niraparib affect NF-κB signaling?",{"text":118,"@type":114},"Niraparib activates NF-κB signaling by inhibiting PARylation of p65, which reduces its ubiquitination and degradation level through the E3 ubiquitin ligase RNF146.",{"name":120,"@type":111,"acceptedAnswer":121},"Why is bortezomib used with niraparib?",{"text":122,"@type":114},"Bortezomib, a small molecule inhibitor of the NF-κB signaling pathway, significantly enhances the anti-tumor effect of niraparib on thyroid cancers in both in vitro and in vivo models.","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},380290,1790318573,{"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":146},1099523885336,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Ivyspring  \nInternational Publisher  \nInternationalJournal of Biological Sciences  \n2023; 19(12): 3970-3986. doi: 10.7150/ijbs.81895  \nResearch Paper  \nPARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause  \nXiukun Hou1\\#, Mengran Tian2,3,4\\#, Junya Ning1,2,3,4\\#, Zhongyu Wang1, Fengli Guo1, Wei Zhang2,3,4, Linfei Hu1, Songfeng Wei1, Chuanxiang Hu1, Xinwei Yun1, Jingzhu Zhao1, Qiman Dong5, Xianhui Ruan1, Dapeng Li1􀀍, Ming Gao1,2,3􀀍, and Xiangqian Zheng1􀀍  \n1. Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300040, China.  \n2. Department of Thyroid and Breast Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.  \n3. Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin,300121, China.  \n4. School of Medicine, Nankai University, Tianjin 300071, China.  \n5. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China.  \n\\#These authors contributed equally to this work.  \n􀀍 Corresponding authors: Dapeng Li, [lidapeng0203@163.com](lidapeng0203@163.com); Ming Gao, [headandneck2008@126.com](headandneck2008@126.com); Xiangqian Zheng, [xzheng05@tmu.edu.cn](xzheng05@tmu.edu.cn).  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2022.12.15; Accepted: 2023.07.18; Published: 2023.07.31  \nAbstract  \nThyroid cancer has become the most frequent endocrine-related malignancy. Currently, a mounting body of evidences support the clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers. However, the functions and molecular mechanisms of PARP inhibitors in thyroid cancers (TCs) are not fully understood. Here, on the one hand, we revealed that niraparib promotes the accumulation of DNA damage in TCs. On the other hand, we indicated that niraparib inhibits the transcription of DIMT1 through promoting Pol II pausing in a PAR-dependent manner, subsequently leading to a global translation inhibition in TCs. Meanwhile, we found that niraparib activates the NF-κB signaling pathway by inhibiting the PARylation of p65, which decreases its ubiquitination and degradation level through E3 ubiquitin ligase RNF146. Moreover, bortezomib (a small molecule inhibitor of the NF-κB signaling pathway) could significantly enhance the anti-tumor effect of niraparib on TCs in vitro and in vivo. Our findings provide mechanistic supports for the efficacy of PARP inhibitors in cancer cells lacking BRCA-mutant.  \nKeywords: PARP inhibitor, BRCAness genes, Pol II pausing, NF-κB signaling pathway, combination treatment  \nIntroduction  \nThe incidence of thyroid cancer has dramatically increased during the past decades. Up to now, TC has become the most frequent endocrine-related malignancy (1) . Based on the histopathological features, TC has been clarified into different subtypes, including papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) . Although the majority of PTCs display a good prognosis, still approximately 15% of them occurred recurrence and with a poor prognosis (2) . Meanwhile, ATCs are highly aggressive and always resistant to conven-  \ntional treatment including radioactive iodine and chemotherapy. Over 90% of ATCs lost the opportunity of surgery at the time of diagnosis and dead in less than one more year (3) . Therefore, searching for a new treatment strategy for TCs i","cbCaijWnSfL0frf0","https://ap.wps.com/l/cbCaijWnSfL0frf0","pdf",10895456,17,"English","# Abstract\n# Keywords\n# Introduction\n## Thyroid cancer background and therapeutic need\n## PARP, PARylation, and transcription regulation\n## Ribosome biogenesis and Pol II function\n## NF-κB signaling in tumor progression","[{\"question\":\"What role does niraparib play in thyroid cancer cells?\",\"answer\":\"Niraparib promotes DNA damage accumulation and suppresses DIMT1 transcription by inducing PAR-dependent Pol II pausing, which leads to global translation inhibition in thyroid cancer cells.\"},{\"question\":\"How does niraparib affect NF-κB signaling?\",\"answer\":\"Niraparib activates NF-κB signaling by inhibiting PARylation of p65, which reduces its ubiquitination and degradation level through the E3 ubiquitin ligase RNF146.\"},{\"question\":\"Why is bortezomib used with niraparib?\",\"answer\":\"Bortezomib, a small molecule inhibitor of the NF-κB signaling pathway, significantly enhances the anti-tumor effect of niraparib on thyroid cancers in both in vitro and in vivo models.\"}]","PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause | PDF",1790239599,43]