{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T09:26:23Z","timestamp":1787217983561,"version":"build-2736575974"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":24,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 ES030335"],"award-info":[{"award-number":["R01 ES030335"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 ES031796"],"award-info":[{"award-number":["R01 ES031796"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 ES019851"],"award-info":[{"award-number":["T32 ES019851"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 CA016520"],"award-info":[{"award-number":["P30 CA016520"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012288","name":"Breast Cancer Coalition","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012288","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["DBG-24-1243614-01-DMC"],"award-info":[{"award-number":["DBG-24-1243614-01-DMC"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"Department of Defense","doi-asserted-by":"publisher","award":["BC201356"],"award-info":[{"award-number":["BC201356"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basser Center for BRCA-related Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The tumor suppressor\u00a0RAD51C is essential for DNA double-strand break repair through the homologous recombination (HR) pathway. RAD51C loss is linked to an increased risk of breast cancer, but the majority of RAD51C missense mutations identified in patients are variants of unknown significance. In addition to promoting HR, RAD51C also protects damaged replication forks. Here, we characterized 33 clinically identified breast cancer variants and assayed their ability to perform HR. We identified one HR-deficient variant and five variants with intermediate HR proficiency. While these variants have modestly attenuated HR, they misregulate replication fork progression and accumulate single-strand DNA gaps. We then assessed their sensitivity to PARP1 and ATR inhibition. While RAD51C variants with attenuated HR are largely resistant to monotherapy, cells expressing a subset of these RAD51C variants exhibit increased sensitivity to combination PARP1i and ATRi treatment, Saruparib and Ceralasertib, respectively. Collectively, we pinpoint the key functional regions of RAD51C and uncover a new C-terminal region proximal to the ATP-binding site in the folded RAD51C structure. Together, our findings suggest that variants with partial HR function can cause profound defects in the repair of replicative damage, and that this, in turn, may lead to distinct therapeutic responses.<\/jats:p>","DOI":"10.1093\/narcan\/zcag018","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T11:46:27Z","timestamp":1786535187000},"source":"Crossref","is-referenced-by-count":0,"title":["RAD51C breast cancer-identified variants with attenuated homologous recombination function exhibit sensitivity to combined PARP1 and ATR inhibition"],"prefix":"10.1093","volume":"8","author":[{"given":"Gayatri S","family":"Ganesan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zo\u00eb R","family":"Moosbrugger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoebe S","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4925-4146","authenticated-orcid":false,"given":"Noah J","family":"Goff","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun\u00a0K","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2247-6459","authenticated-orcid":false,"given":"Kara A","family":"Bernstein","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA 19104,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"2026082004553284400_B1","doi-asserted-by":"publisher","first-page":"e2202727119","DOI":"10.1073\/pnas.2202727119","article-title":"Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants","volume":"119","author":"Prakash","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026082004553284400_B2","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1038\/s41586-023-06219-w","article-title":"Structural insights into BCDX2 complex function in homologous recombination","volume":"619","author":"Rawal","year":"2023","journal-title":"Nature"},{"key":"2026082004553284400_B3","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1038\/s41467-020-17324-z","article-title":"Sequential role of RAD51 paralog complexes in replication fork remodeling and restart","volume":"11","author":"Berti","year":"2020","journal-title":"Nat Commun"},{"key":"2026082004553284400_B4","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1056\/NEJMoa1913948","article-title":"Breast cancer risk genes\u2014association analysis in more than 113,000 women","volume":"384","author":"Breast Cancer Association, C.","year":"2021","journal-title":"N Engl J Med"},{"key":"2026082004553284400_B5","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1056\/NEJMoa2005936","article-title":"A population-based study of genes previously implicated in breast cancer","volume":"384","author":"Hu","year":"2021","journal-title":"N Engl J Med"},{"key":"2026082004553284400_B6","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1158\/1078-0432.CCR-13-2287","article-title":"Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas","volume":"20","author":"Pennington","year":"2014","journal-title":"Clin Cancer Res"},{"key":"2026082004553284400_B7","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1136\/jmg.2004.024711","article-title":"Classification of BRCA1 missense variants of unknown clinical significance","volume":"42","author":"Phelan","year":"2005","journal-title":"J Med 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