[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-detail-165125-en":3,"doc-seo-165125-105":30,"detail-sidebar-cat-1-en-105":92},{"code":4,"msg":5,"data":6},0,"success",{"doc_id":7,"user_id":8,"nickname":9,"user_avatar":10,"doc_module":11,"category_id":12,"category_name":13,"doc_title":14,"doc_description":15,"doc_content":16,"file_id":17,"file_url":18,"file_type":19,"file_size":20,"view_count":4,"is_deleted":4,"is_public":11,"is_downloadable":11,"audit_status":11,"page_count":21,"language":22,"language_code":23,"site_id":24,"html_lang":23,"table_of_contents":25,"faqs":26,"seo_title":27,"seo_description":15,"update_tm":28,"read_time":29},165125,687197207919,"Theodora","https://ap-avatar.wpscdn.com/avatar/a000253d6f5f7c60be?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779446848396160552",1,158,"General","Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality","PARP inhibitors (PARPi) have entered clinical practice for homologous recombination (HR)-deficient cancers, yet resistance limits durable benefit. Combined genetic screens with multi-omics profiling of matched BRCA2-mutated mouse mammary tumors identified loss of PARG as a major resistance driver. PARG-negative clones were also detected in subgroups of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling, while PARG inactivation creates exploitable therapeutic vulnerabilities.","Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality\nEwa Gogola1,14, Alexandra A. Duarte1,14,16, Julian R. de Ruiter1,2,14,16, Wouter W. Wiegant6, Jonas A. Schmid7, Roebi de Bruijn1,2,14, Dominic I. James8, Sergi Guerrero Llobet9, Daniel J. Vis2,14, Stefano Annunziato1,14, Bram van den Broek3, Marco Barazas1,14, Ariena Kersbergen5, Marieke van de Ven4, Madalena Tarsounas10, Donald J. Ogilvie8, Marcel van Vugt9, Lodewyk F.A. Wessels2,14, Jirina Bartkova11,12, Irina Gromova11, Miguel Andújar Sánchez13, Jiri Bartek11,12, Massimo Lopes7, Haico van Attikum6, Piet Borst5, Jos Jonkers1,14* and Sven Rottenberg1,15,*,#\nAuthors’ affiliations: 1Division of Molecular Pathology; 2Division of Molecular Carcinogenesis; 3Division of Cell Biology and BioImaging Facility; 4Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit; 5Division of Molecular Oncology, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands; 6Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands; 7Institute of Molecular Cancer Research, University of Zurich, CH-8057 Zurich, Switzerland; 8Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, M20 4BX Manchester, United Kingdom; 9Department of Medical Oncology, University Medical Center Groningen, University of Groningen, 9723GZ Groningen, The Netherlands; 10CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, OX3 7DQ Oxford, United Kingdom; 11Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; 12Karolinska Institute, Department of Medical Biochemistry and Biophysics, Division of Genome Biology, Science for Life, Laboratory, 171 77 Stockholm, Sweden; 13Pathology Department, Complejo Hospt. Univ. Insular Materno Infantil, Las Palmas de Gran Canaria, Spain; 14Cancer Genomics Netherlands, Oncode Institute, 1066CX Amsterdam, The Netherlands; 15Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; 16these authors contributed equally to this work.\n*Correspondence: \u0013 HYPERLINK \"mailto:sven.rottenberg@vetsuisse.unibe.ch\" \u0014sven.rottenberg@vetsuisse.unibe.ch\u0015 (SR), \u0013 HYPERLINK \"mailto:j.jonkers@nki.nl\" \u0014j.jonkers@nki.nl\u0015 (JJ)\n#Lead contact\u000f\nSUMMARY\nInhibitors of poly(ADP-ribose) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of poly(ADP-ribose) glycohydrolase (PARG) as a major resistance mechanism. We also found the presence of PARG-negative clones in a subset of human serous ovarian and triple-negative breast cancers. PARG depletion restores PAR formation and partially rescues PARP1 signaling. Importantly, PARG inactivation exposes vulnerabilities that can be exploited therapeutically.\nSIGNIFICANCE\nTo explore defects in the DNA damage response in cancer therapy, exciting opportunities have been achieved using the “synthetic lethal” approach. A successful example is the development of PARP inhibitors to kill cancer cells that are defective in HR, e.g. due to lack of function of BRCA1 or BRCA2. Thus, there is a real opportunity to cure patients with HR-deficient cancers if we overcome the hurdle of drug resistance. At present, it is largely unknown how tumor cells escape PARP inhibition without restoring BRCA2-mediated HR. Here, we show that loss of PARG governs PARPi resistance in HR-deficient tumors by restoring PARP1 signaling. Importantly, inactivation of PARG results in vulnerabilities that can be exploited to combat resistance.\nKeywords: BRCA1; BRCA2; PARG; PARP1; PARP inhibitor; drug resistance; PA","cbCailFSV4RC5f2k","https://ap.wps.com/l/cbCailFSV4RC5f2k","docx",241031,46,"English","en",105,"# Summary\n# Significance\n# Introduction","[{\"question\":\"Why are PARP inhibitors effective in HR-deficient cancers, and what limits their success?\",\"answer\":\"PARP inhibitors exploit defects in homologous recombination, making HR-deficient cells vulnerable. Drug resistance remains a clinical hurdle and reduces long-term effectiveness.\"},{\"question\":\"What was identified as a major mechanism of resistance to PARP inhibitors in the study?\",\"answer\":\"Loss of PARG emerged as a major resistance mechanism through genetic screens and multi-omics analysis of matched PARPi-sensitive and PARPi-resistant BRCA2-mutated tumors.\"},{\"question\":\"How does PARG depletion affect PAR formation and PARP1 signaling?\",\"answer\":\"PARG depletion restores PAR formation and partially rescues PARP1 signaling, and PARG inactivation reveals therapeutic vulnerabilities that can be exploited to counter resistance.\"}]","Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality | DOCX",1788166538,16,{"code":4,"msg":31,"data":32},"ok",{"site_id":24,"language":23,"slug":33,"title":14,"keywords":34,"description":15,"schema_data":35,"social_meta":87,"head_meta":89,"extra_data":91,"updated_unix":28},"selective-loss-of-parg-restores-parylation-and-counteracts-parp-inhibitor-mediated-synthetic-lethality","",{"@graph":36,"@context":86},[37,54,69],{"@type":38,"itemListElement":39},"BreadcrumbList",[40,44,48,51],{"item":41,"name":42,"@type":43,"position":11},"https://docshare.wps.com","Home","ListItem",{"item":45,"name":46,"@type":43,"position":47},"https://docshare.wps.com/template/","Template",2,{"item":49,"name":13,"@type":43,"position":50},"https://docshare.wps.com/template/general/",3,{"item":52,"name":14,"@type":43,"position":53},"https://docshare.wps.com/template/selective-loss-of-parg-restores-parylation-and-counteracts-parp-inhibitor-mediated-synthetic-lethality/165125/",4,{"url":52,"name":14,"@type":55,"author":56,"headline":14,"publisher":58,"fileFormat":61,"inLanguage":23,"description":15,"dateModified":62,"datePublished":63,"encodingFormat":61,"isAccessibleForFree":64,"interactionStatistic":65},"DigitalDocument",{"name":9,"@type":57},"Person",{"url":41,"name":59,"@type":60},"DocShare","Organization","application/vnd.openxmlformats-officedocument.wordprocessingml.document","2026-09-04","2026-08-31",true,{"@type":66,"interactionType":67,"userInteractionCount":47},"InteractionCounter",{"@type":68},"ViewAction",{"@type":70,"mainEntity":71},"FAQPage",[72,78,82],{"name":73,"@type":74,"acceptedAnswer":75},"Why are PARP inhibitors effective in HR-deficient cancers, and what limits their success?","Question",{"text":76,"@type":77},"PARP inhibitors exploit defects in homologous recombination, making HR-deficient cells vulnerable. Drug resistance remains a clinical hurdle and reduces long-term effectiveness.","Answer",{"name":79,"@type":74,"acceptedAnswer":80},"What was identified as a major mechanism of resistance to PARP inhibitors in the study?",{"text":81,"@type":77},"Loss of PARG emerged as a major resistance mechanism through genetic screens and multi-omics analysis of matched PARPi-sensitive and PARPi-resistant BRCA2-mutated tumors.",{"name":83,"@type":74,"acceptedAnswer":84},"How does PARG depletion affect PAR formation and PARP1 signaling?",{"text":85,"@type":77},"PARG depletion restores PAR formation and partially rescues PARP1 signaling, and PARG inactivation reveals therapeutic vulnerabilities that can be exploited to counter resistance.","https://schema.org",{"og:url":52,"og:type":88,"og:title":14,"og:site_name":59,"og:description":15},"article",{"robots":90,"canonical":52},"index,follow",{"doc_id":7,"site_id":24},{"code":4,"msg":5,"data":93},[94,99,104,109,114,118,123,128,133],{"id":95,"doc_module":11,"doc_module_name":46,"category_name":96,"show_sort_weight":97,"slug":98},11,"Presentations",90,"presentations",{"id":100,"doc_module":11,"doc_module_name":46,"category_name":101,"show_sort_weight":102,"slug":103},12,"Resumes",80,"resumes",{"id":105,"doc_module":11,"doc_module_name":46,"category_name":106,"show_sort_weight":107,"slug":108},14,"Invoices",70,"invoices",{"id":110,"doc_module":11,"doc_module_name":46,"category_name":111,"show_sort_weight":112,"slug":113},15,"Posters",60,"posters",{"id":29,"doc_module":11,"doc_module_name":46,"category_name":115,"show_sort_weight":116,"slug":117},"Social Media",50,"social-media",{"id":119,"doc_module":11,"doc_module_name":46,"category_name":120,"show_sort_weight":121,"slug":122},17,"Forms",40,"forms",{"id":124,"doc_module":11,"doc_module_name":46,"category_name":125,"show_sort_weight":126,"slug":127},18,"Letters",30,"letters",{"id":129,"doc_module":11,"doc_module_name":46,"category_name":130,"show_sort_weight":131,"slug":132},21,"Paper Templates",5,"papers-templates",{"id":12,"doc_module":11,"doc_module_name":46,"category_name":13,"show_sort_weight":4,"slug":134},"general-158"]