BRCA1 separation-of-function alleles in stalled fork repair and FANCM synthetic lethality
BRCA1 mutant cancers, but not those lacking BRCA2, contain abundant 10 kb (Group 1) tandem duplications (TDs). Group 1 TDs form at a site-specific Tus/Ter replication fork barrier in mouse embryonic stem (mES) cells lacking Brca1 exon 11 (Del11), which are defective for DNA end resection. To explore relationships between DNA end resection and Group 1 TD formation, we analyzed Brca1 coiled coil (CC) domain mutants, in which PALB2 binding and RAD51 loading for homologous recombination are impaired, but DNA end resection is intact. In contrast to Brca1 Del11 mutants, Brca1 CC mutants retain the ability to suppress Tus/Ter-induced TDs. Further, mouse mammary tumors driven by a Brca1 CC mutant, L1363P, do not reveal a Group 1 TD phenotype. FANCM is a TD co-suppressor in Brca1 Del11 mES cells and Fancm loss is synthetic lethal/sick in combination with Brca1 Del11 mutation. In contrast, Fancm deletion is well-tolerated by Brca1 L1363P mES cells. These findings suggest that Group 1 TD formation and Fancm synthetic lethality are linked phenotypes arising from defective BRCA1-mediated DNA end resection.