FANCM regulates repair pathway choice at stalled replication forks

Repair pathway choice at stalled mammalian forks is an important determinant of genome stability; however, the mechanisms underlying this choice are poorlyunderstood. The Fanconi anemia complementation group M gene, FANCM , encodes a multi-domain scaffolding and motor protein that interacts with several distinct repairprotein complexes at stalled forks. Here we use a chromosomally integrated reporter of stalled fork repair, in combination with defined mutations engineered withinendogenous Fancm in primary mammalian cells, to study how Fancm regulates stalled fork repair. We find that distinct repair functions of FANCM are enacted bymolecularly separable scaffolding domains. These findings define FANCM as a key mediator of repair pathway choice at stalled replication forks and reveal its molecularmechanism. Notably, mutations that inactivate the ATPase function of FANCM disable all its repair functions and trap FANCM at stalled forks. We find that Brca1hypomorphic mutants are inviable on a Fancm null background. This synthetic lethal interaction is recapitulated in Fancm ATPase-defective mutants. The ATPase functionof FANCM may therefore represent a promising druggable target for therapy of BRCA1 mutant cancers.