A genome-scale adaptation map identifies the FANCM-RMI1/2 complex as an opposing modulator of cell fitness upon BRCA1 or BRCA2 loss.

Cancer cells lacking BRCA1 or BRCA2 must adapt to proliferate despite pervasive genomic instability. To delineate BRCA1- and BRCA2-specific adaptation landscapes, we developed an isogenic screening platform enabling acute depletion of either protein. Genetic interaction profiling revealed hundreds of genes with shared, distinct, or opposing effects in the two BRCA-deficient states. We identified FANCM as essential in BRCA1-deficient cells. Conversely, FANCM is toxic in BRCA2-deficient cells, where it promotes replication fork degradation through RMI1/2 recruitment and sensitizes cells to PARP inhibition. FANCM loss restored fork integrity and alleviated genomic instability and proliferation defects without restoring homologous recombination or suppressing single-stranded DNA (ssDNA) gaps. Finally, we report a FANCM variant that disrupts RMI1/2 binding in a BRCA2m breast cancer patient that is associated with PARP-inhibitor resistance. These findings define fundamentally distinct adaptive routes to BRCA1 and BRCA2 loss and establish FANCM-RMI1/2 as a determinant of mutation-specific vulnerabilities and therapeutic responses.