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

FANCM-RMI1/2 complex acts as a critical opposing modulator of cell survival in BRCA2-deficient cells, with 200+ genes showing distinct effects in BRCA1- and BRCA2-loss contexts.

• Why it matters: Understanding how cancer cells adapt to BRCA1 or BRCA2 loss is vital for developing targeted therapies, especially since these deficiencies cause significant genomic instability and influence treatment responses.
• What they did: Using an isogenic screening platform, the study performed genetic interaction profiling on cells with acute BRCA1 or BRCA2 depletion, identifying hundreds of genes with differential effects, including the essential role of FANCM in BRCA1-deficient cells and its toxicity in BRCA2-deficient cells.
• The result: Loss of FANCM improved replication fork stability and reduced genomic instability in BRCA2-deficient cells, revealing mutation-specific vulnerabilities and suggesting that targeting FANCM-RMI1/2 could influence therapeutic strategies like PARP inhibition resistance.