FANCM restrains structural genome evolution and defines a synthetic lethal dependency in BRCA1-deficient breast cancer
BRCA1 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/FANCM synthetic lethality in human BRCA1 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 BRCA1 deficient breast cancer cells under endogenous replication stress. FANCM loss amplifies the characteristic BRCA1 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 BRCA1 mutant breast cancer cells, linking FANCM-mediated genome protection to transcription replication encounters. BRCA1 altered human tumors with low FANCM expression recapitulate key features of this phenotype, while genome/transcriptome 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.