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Grohne Cancer Immunology and Immunotherapy Program","award":["T32 GM065841"],"award-info":[{"award-number":["T32 GM065841"]}]},{"DOI":"10.13039\/100007048","name":"Mayo Foundation for Research and Education","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007048","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>BRCA2 mutations contribute to the pathogenesis and treatment sensitivity of a subset of ovarian, breast, prostate, and pancreatic cancers. When these cancers become therapy resistant, secondary mutations that restore the BRCA2 open reading frame are found in half the cases, but other causes of resistance remain incompletely understood. Here, we identified translational readthrough of a premature termination codon (PTC) as a cause of resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) and cisplatin in cells derived from the BRCA2-mutated ovarian cancer line PEO1 by PARPi selection. Despite persistence of the signature 4965C\u00a0&amp;gt;\u00a0G (p.Y1655X) BRCA2 mutation, low-level expression of full-length BRCA2 protein was detectable in these cells by immunoblotting and tandem mass spectrometry. Either BRCA2 knockdown or gene interruption 5\u2032 or 3\u2032 to the PTC restored treatment sensitivity, implicating BRCA2 in the resistance. Reporter assays demonstrated UAG-selective readthrough in the resistant clones but not parental cells. Moreover, custom searching of global proteomic data indicated readthrough of stop codons, particularly UAGs, in additional proteins in the resistant clones. Finally, multi-omic analysis identified multiple changes in the nonsense-mediated decay and termination machineries that favor readthrough. Accordingly, the present results identify PTC readthrough as a potential mechanism of drug resistance in cells with BRCA2 nonsense mutations.<\/jats:p>","DOI":"10.1093\/nar\/gkaf990","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T17:53:45Z","timestamp":1760550825000},"source":"Crossref","is-referenced-by-count":2,"title":["Codon specific readthrough as a mechanism of BRCA2 restoration in acquired PARP inhibitor and chemotherapy resistance"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-8333","authenticated-orcid":false,"given":"Cordelia\u00a0D","family":"McGehee","sequence":"first","affiliation":[{"name":"Mayo Clinic Department of Molecular Pharmacology & Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X\u00a0Wei","family":"Meng","sequence":"additional","affiliation":[{"name":"Mayo Clinic Department of Molecular Pharmacology & Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]},{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Mayo Clinic Department of Molecular Pharmacology & Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]},{"name":"Mayo Clinic Department of Laboratory Medicine & Pathology, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9464-7555","authenticated-orcid":false,"given":"Cristina","family":"Correia","sequence":"additional","affiliation":[{"name":"Mayo Clinic Department of Molecular Pharmacology & Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]},{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapoorna","family":"Venkatachalam","sequence":"additional","affiliation":[{"name":"Mayo Clinic Department of Molecular Pharmacology & Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]},{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen\u00a0S","family":"Flatten","sequence":"additional","affiliation":[{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin\u00a0L","family":"Peterson","sequence":"additional","affiliation":[{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United 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& Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill\u00a0M","family":"Wagner","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology , Mayo Clinic,\u00a0Rochester,\u00a0MN 55905,\u00a0","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula\u00a0A","family":"Schneider","sequence":"additional","affiliation":[{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Dai","sequence":"additional","affiliation":[{"name":"Division of Oncology Research , Mayo Clinic,\u00a0 Rochester , MN 55905 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy\u00a0G","family":"Poirier","sequence":"additional","affiliation":[{"name":"Oncology Division, CHU de Qu\u00e9bec Research Centr ,\u00a0Quebec G1V 4G2,\u00a0","place":["Canada"]},{"name":"e, CHUL Pavillion ,\u00a0Quebec G1V 4G2,\u00a0","place":["Canada"]},{"name":"Medical Biology and Pathology, Faculty of Medicine, University Laval Department of Molecular Biology, ,\u00a0Quebec G1V 4G2,\u00a0","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea\u00a0E\u00a0Wahner","family":"Hendrickson","sequence":"additional","affiliation":[{"name":"Mayo Clinic Department of Molecular Pharmacology & Experimental Therapeutics, ,\u00a0 Rochester , MN 55905 ,","place":["United States"]},{"name":"Division of Medical Oncology , Mayo Clinic,\u00a0Rochester,\u00a0MN 55905,\u00a0","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth\u00a0M","family":"Swisher","sequence":"additional","affiliation":[{"name":"University of Washington Department of Obstetrics & Gynecology, ,\u00a0Seattle,\u00a0WA 98195,\u00a0","place":["United 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