{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T02:08:45Z","timestamp":1780538925116,"version":"3.54.1"},"reference-count":175,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T00:00:00Z","timestamp":1780185600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015800","name":"Science and Technology Development Plan Project of Jilin Province","doi-asserted-by":"publisher","award":["YDZJ202201ZYTS658"],"award-info":[{"award-number":["YDZJ202201ZYTS658"]}],"id":[{"id":"10.13039\/100015800","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010211","name":"Scientific Research Project of Jilin Provincial Department of Education","doi-asserted-by":"publisher","award":["JJKH20251044KJ"],"award-info":[{"award-number":["JJKH20251044KJ"]}],"id":[{"id":"10.13039\/501100010211","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Germline loss-of-function mutations in BRCA1 and BRCA2 markedly increase susceptibility to breast, ovarian, and other cancers. Mechanistically, BRCA2 facilitates RAD51 recruitment to sites of DNA damage, whereas BRCA1 regulates homologous recombination repair (HRR) through double-strand break resection and broader DNA damage response signaling. These insights underpin targeted therapies such as poly (ADP-ribose) polymerase inhibitors (PARPis), which induce synthetic lethality in homologous recombination-deficient tumors. Clinically, PARPis have demonstrated significant benefit in BRCA1\/2-mutated breast, ovarian, pancreatic, and prostate cancers. However, resistance remains a major obstacle, with secondary intragenic BRCA1\/2 mutations restoring partial protein function representing a prominent mechanism. Despite therapeutic advances, critical gaps persist in understanding how specific BRCA1\/2 domains and residual protein activities contribute to tumorigenesis and treatment response. In this review, we summarize the structural and functional domains of BRCA1\/2, their pathogenic mutation profiles, and therapeutic strategies targeting BRCA1\/2-deficient cancers. Despite therapeutic advances, critical gaps persist in understanding how specific BRCA1\/2 domains and residual protein activities contribute to tumorigenesis and treatment response. This review emphasizes the need for functional studies of BRCA1\/2 variants to refine risk prediction and develop mutation-tailored therapies.<\/jats:p>","DOI":"10.3390\/biology15110866","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BRCA1\/2 Reversion Mutations and Cancer Therapy Resistance"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6438-946X","authenticated-orcid":false,"given":"Wenjing","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Bioscience, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gege","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin H.","family":"Mayo","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Changchun Normal University, Changchun 130032, China"},{"name":"Biochemistry, Molecular Biology, and Biophysics, Health Sciences Center, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2655-4197","authenticated-orcid":false,"given":"Xianlu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Epigenetics of Ministry of Education, College of Life Sciences, Northeast Normal University, Changchun 130024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1873-6928","authenticated-orcid":false,"given":"Jingang","family":"Mo","sequence":"additional","affiliation":[{"name":"Department of Bioscience, Changchun Normal University, Changchun 130032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1126\/science.7545954","article-title":"A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1","volume":"266","author":"Miki","year":"1994","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1126\/science.8091231","article-title":"Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13","volume":"265","author":"Wooster","year":"1994","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1001\/jamaoncol.2024.2185","article-title":"BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients: A Review","volume":"10","author":"Cheng","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1200\/JCO-24-01334","article-title":"Clinical Behavior of Breast Cancer in Young BRCA Carriers and Prediagnostic Awareness of Germline BRCA Status","volume":"43","author":"Lambertini","year":"2025","journal-title":"J. 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