loading . . . The FANCM-RMI1/2 complex promotes genomic instability and PARP inhibitor sensitivity in BRCA2-deficicient cells. Cancer cells lacking BRCA1 or BRCA2 must adapt to survive and proliferate despite defective DNA repair and high genomic instability. Restoration of homologous recombination (HR) through loss of DNA end protection rescues growth defects and promotes PARP inhibitor (PARPi) resistance in BRCA1-deficient cells; however, the genetic basis of adaptation to BRCA2 loss remains largely unexplored. To delineate BRCA1- and BRCA2-specific adaptation trajectories, we established a fully isogenic screening platform in mouse embryonic stem cells engineered for acute depletion of either protein. This approach uncovered hundreds of genes with shared, distinct, or even opposing effects between the two BRCA-deficiency states. We identified FANCM and its interacting partners RMI1/2, CENPS/MHF1, CENPX/MHF2, and FAAP24 as essential in BRCA1-deficient cells but toxic in BRCA2- deficient contexts. Loss of FANCM in BRCA2-deficient cells alleviated genomic instability and proliferation defects by preventing RMI1/2-dependent replication fork degradation, without rescuing HR. Moreover, we show that the FANCM-RMI1/2 complex drives PARPi sensitivity in both mouse and human BRCA2-deficient cells, in contrast to the 53BP1-SHLD-CST axis in BRCA1-deficient cells. These findings reveal distinct adaptation routes to BRCA1 and BRCA2 loss and establish FANCM as a determinant of BRCA2-specific vulnerability and therapeutic response, with direct implications for tailoring prevention and therapy according to BRCA mutation status. ### Competing Interest Statement C.J.L. makes the following disclosures: receives and/or has received research funding from: AstraZeneca, Merck KGaA, Artios, Neophore, FoRx. Received consultancy, SAB membership or honoraria payments from: FoRx, Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango Therapeutics, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, Glaxo Smith Kline, Dawn Bioventures, Blacksmith Medicines, ForEx, Ariceum. Has stock in: Tango, Ovibio, Hysplex, Tesselate, Ariceum. C.J.L. is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR Rewards to Inventors scheme and also reports benefits from this scheme associated with patents for PARP inhibitors paid into CJL's personal account and research accounts at the Institute of Cancer Research. 020 https://www.biorxiv.org/content/10.64898/2026.01.15.699681v1
