{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:06:16Z","timestamp":1789236376577,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,10]]},"group-title":"Cancer Biology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute of the National Institutes of Health","award":["R00CA252044"],"award-info":[{"award-number":["R00CA252044"]}]},{"name":"Career Enhancement Program of the Mayo Clinic Breast Cancer SPORE","award":["P50CA116201"],"award-info":[{"award-number":["P50CA116201"]}]},{"name":"Pilot Project supported through the Mayo Clinic Comprehensive Cancer Center (MCCCC) under the National Cancer Institute","award":["P30CA015083"],"award-info":[{"award-number":["P30CA015083"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>BRCA1<\/jats:italic>\n                  -deficient cancers experience persistent replication stress and structural genome instability yet retain the capacity for sustained proliferation, implying reliance on compensatory genome-maintenance mechanisms. Here, we establish BRCA1\u2013FANCM synthetic lethality in human\n                  <jats:italic>BRCA1<\/jats:italic>\n                  -deficient breast cancer and exploit temporally controlled FANCM depletion to capture genome evolution over successive cell divisions before declining cellular fitness becomes limiting. We show that FANCM restrains genome-wide structural variation in\n                  <jats:italic>BRCA1<\/jats:italic>\n                  -deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic\n                  <jats:italic>BRCA1<\/jats:italic>\n                  -associated short tandem duplication (TD) phenotype while permitting larger, including megabase-scale, TDs and diverse rearrangements to emerge. Newly emerged TDs preferentially associate with Pol II-occupied regions, and FANCM depletion increases proximity between the replication machinery and elongating RNAPII in\n                  <jats:italic>BRCA1<\/jats:italic>\n                  -mutant breast cancer cells, linking FANCM-mediated genome protection to transcription\u2013replication encounters.\n                  <jats:italic>BRCA1<\/jats:italic>\n                  -altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome\u2013transcriptome integration links newly emerged SVs to configuration-dependent local transcriptional changes. Together, these findings establish FANCM as a replication-stress safeguard coupling survival to restraint of structural genome evolution.\n                <\/jats:p>","DOI":"10.64898\/2026.09.06.749689","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:35:18Z","timestamp":1789072518000},"source":"Crossref","is-referenced-by-count":0,"title":["FANCM restrains structural genome evolution and defines a synthetic lethal dependency in\n                  <i>BRCA1<\/i>\n                  -deficient breast cancer"],"prefix":"10.64898","author":[{"given":"Farah","family":"Ramadan","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer Bikram","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ujwal","family":"Subedi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary D.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapoorna","family":"Venkatachalam","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelima","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, 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