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This study examines whether DNA damage responses intensify in precancerous HPV-positive epithelium and evaluates how HPV16 E7 affects double-strand break repair, homologous recombination competence, and sensitivity to PARP inhibition.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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biological question does the study address?","Question",{"text":63,"@type":64},"The study investigates how HPV16 E7 influences DNA damage responses and double-strand break repair in precancerous and cervical cell contexts, and whether this leads to homologous recombination defects and PARP inhibitor sensitivity.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How was E7’s effect on DNA repair assessed?",{"text":68,"@type":64},"The researchers biopsied and cryosectioned cervical tissues for immunofluorescent staining, then expressed HA-tagged HPV16 E6/E7 in cell models and used indirect immunofluorescent staining to evaluate double-strand break repair competency.",{"name":70,"@type":61,"acceptedAnswer":71},"What is the key finding regarding PARPi sensitivity?",{"text":72,"@type":64},"E7 expression is associated with homologous recombination deficiency in HPV-negative cervical cells, and E7-expressing cells show reduced viability upon exposure to PARP inhibitors compared with 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Oncology (2024) 150:27  \n[https://doi.org/10.1007/s00432-023-05511-6](https://doi.org/10.1007/s00432-023-05511-6)  \nHuman papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity  \nSiqi He1 · Ao Wang1 · Jing Wang2 · Zizhi Tang1 · Xiaojun Wang1 · Danqing Wang1 · Jie Chen1 · Cong Liu1 · Mingcai Zhao2 · Hui Chen1 · Liang Song1  \nReceived: 25 September 2023 / Accepted: 8 November 2023 / Published online: 23 January 2024 © The Author(s) 2024  \nAbstract  \nPurpose Cervical cancer is a common gynecological malignancy, pathologically associated with persistent infection of highrisk types of human papillomavirus (HPV) . Previous studies revealed that HPV-positive cervical cancer displays genomic instability; however, the underlying mechanism is not fully understood.  \nMethods To investigate if DNA damage responses are aggravated in precancerous lesions of HPV-positive cervical epithelium, cervical tissues were biopsied and cryosectioned, and subjected to immunofluorescent staining. Cloned HA-tagged E6 and E7 genes of HPV16 subtype were transfected into HEK293T or C33A cells, and indirect immunofluorescent staining was applied to reveal the competency of double strand break (DSB) repair. To test the synthetic lethality of E7-indued HRD and PARP inhibitor (PARPi), we expressed E7 in C33A cells in the presence or absence of olaparib, and evaluated cell viability by colony formation.  \nResults In precancerous lesions, endogenous DNA lesions were elevated along with the severity of CIN grade. Expressing high-risk viral factor (E7) in HPV-negative cervical cells did not impair checkpoint activation upon genotoxic insults, but affected the potential of DSB repair, leading to homologous recombination deficiency (HRD) . Based on this HPV-induced genomic instability, the viability of E7-expressing cells was reduced upon exposure to PARPi in comparison with control cells.  \nConclusion In aggregate, our findings demonstrate that HPV-E7 is a potential driver for genome instability and provides anew angle to understand its role in cancer development. The viral HRD could be employed to target HPV-positive cervical cancer via synthetic lethality.  \nKeywords HPV · DNA repair · Checkpoint · PARP inhibitor · cervical cancer  \nSiqi He, Ao Wang, Jing Wang have contributed equally to this work.  \n* Mingcai Zhao [112068366@qq.com](112068366@qq.com)  \n* Hui Chen[chenhui2022@scu.edu.cn](chenhui2022@scu.edu.cn)  \n* Liang Song [drsongliang@163.com](drsongliang@163.com)  \n1 Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), Department of Gynecology and Obstetrics, Meishan Women and Children’s Hospital, West China Second University Hospital, Sichuan University, Chengdu 610041, People’s Republic of China  \n2 Department of Clinical Laboratory, Suining Central Hospital, Suining 629000, People’s Republic of China  \nAbbreviations  \nHPV Human papillomavirus  \nPARPi Poly(ADP-ribose) polymerase inhibitor ATM Ataxia telangiectasia mutated  \nBER Base excision repair  \nATR Ataxia telangiectasia-related CIN Cervical intraepithelial neoplasia IR Ionizing radiation  \nHRD Homologous recombination defect  \nssDNA Single-strand DNA CPT Camptothecin  \nuH2B H2B monoubiquitination IF Inflammatory lesion  \nRPA Replication protein A  \nIntroduction  \nCervical cancer is an aggressive gynecological malignancy. The incidence of cervical cancer has been increasing in recent years, despite prospective decrease with the protection of HPV vaccination. More than 90% of cervical cancers are associated with high-risk human papillomavirus, which encodes two critical oncoproteins, E6 and E7 (Li et al. 2017 ; Yugawa and Kiyono 2009) . E6 is reported to promote p53 degradation, while E7 binds to DNMT1 and increases DNA methylation, leading to inactivation of CpG island (Dueñas-González et al. 2005 ; Leonard et al. 2012 ; Burgers et al. 2007) . In addition, cervix cancer display genom","cbCaivTxQC5RRS4P","https://ap.wps.com/l/cbCaivTxQC5RRS4P","pdf",2614658,"English","# Abstract\n## Purpose\n## Methods\n## Results\n## Conclusion\n# Introduction\n## HPV oncoproteins and genomic instability\n## DNA damage response and homologous recombination\n## Synthetic lethality using PARP inhibitors","[{\"question\":\"What biological question does the study address?\",\"answer\":\"The study investigates how HPV16 E7 influences DNA damage responses and double-strand break repair in precancerous and cervical cell contexts, and whether this leads to homologous recombination defects and PARP inhibitor sensitivity.\"},{\"question\":\"How was E7’s effect on DNA repair assessed?\",\"answer\":\"The researchers biopsied and cryosectioned cervical tissues for immunofluorescent staining, then expressed HA-tagged HPV16 E6/E7 in cell models and used indirect immunofluorescent staining to evaluate double-strand break repair competency.\"},{\"question\":\"What is the key finding regarding PARPi sensitivity?\",\"answer\":\"E7 expression is associated with homologous recombination deficiency in HPV-negative cervical cells, and E7-expressing cells show reduced viability upon exposure to PARP inhibitors compared with control cells.\"}]","Human papillomavirus E7 protein induces homologous recombination defects and PARPi sensitivity | PDF",1790000660]