{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T12:22:03Z","timestamp":1778674923704,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,2]]},"group-title":"Cancer Biology","reference-count":38,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T00:00:00Z","timestamp":1777680000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000048","name":"American Cancer Society","doi-asserted-by":"crossref","award":["133396-RSG-19-029-01-DMC"],"award-info":[{"award-number":["133396-RSG-19-029-01-DMC"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL131744-05"],"award-info":[{"award-number":["R01HL131744-05"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R21AG095841-01"],"award-info":[{"award-number":["R21AG095841-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Reversion mutations that restore BRCA2 function represent a major mechanism of resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) in\n                  <jats:italic>BRCA2<\/jats:italic>\n                  -mutant cancers. Predicting these events could inform treatment strategies, identify patients at increased risk of acquiring PARPi resistance, and improve interpretation of secondary variants. Here, we use an isogenic cell system and CRISPR editing to define the principles governing\n                  <jats:italic>BRCA2<\/jats:italic>\n                  reversion. We show that local sequence context dictates the spectrum of reversions, whereas domain architecture determines which events confer PARPi resistance. We characterize two routes of reversion that operate both within and across exons: DNA-level reading-frame restoration and transcript-level rescue via alternative splicing. Lastly, we identify distinct exon 11 reversion mechanisms, including large genomic deletions and recurrent splice isoforms predicted to remove all eight BRC repeats. These findings define a predictive code for\n                  <jats:italic>BRCA2<\/jats:italic>\n                  reversion and PARPi resistance.\n                <\/jats:p>","DOI":"10.64898\/2026.04.29.721733","type":"posted-content","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T16:50:15Z","timestamp":1777740615000},"source":"Crossref","is-referenced-by-count":0,"title":["Decoding the\n                  <i>BRCA2<\/i>\n                  reversion principles underlying PARP inhibitor resistance"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5984-9434","authenticated-orcid":false,"given":"Anna Gabrielle","family":"Horacek","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley; Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances Li","family":"Kueper","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley; Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7483-9691","authenticated-orcid":false,"given":"Robert","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley; Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2451-5744","authenticated-orcid":false,"given":"Isabella Paige","family":"Lamont","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley; Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella","family":"Tran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanqin","family":"Li","sequence":"additional","affiliation":[{"name":"Innovative Genomic Institute, University of California, Berkeley; Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-5092","authenticated-orcid":false,"given":"Dirk","family":"Hockemeyer","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley; Berkeley, CA 94720, USA"},{"name":"Innovative Genomic Institute, University of California, Berkeley; Berkeley, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051304551117000_2026.04.29.721733v2.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706450"},{"key":"2026051304551117000_2026.04.29.721733v2.2","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1200\/JCO.2015.65.0747","article-title":"Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer","volume":"34","year":"2016","journal-title":"J. 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