FANCM branchpoint translocase: Master of traverse, reverse and adverse DNA repair

Abstract

FANCM is a multifunctional DNA repair enzyme that acts as a sensor and coordinator of replication stress responses, especially interstrand crosslink (ICL) repair mediated by the Fanconi anaemia (FA) pathway. Its specialised ability to bind and remodel branched DNA structures enables diverse genome maintenance activities. Through ATP-powered “branchpoint translocation”, FANCM can promote fork reversal, facilitate replication traverse of ICLs, resolve deleterious R-loop structures, and restrain recombination. These remodelling functions also support a role as sensor of perturbed replication, eliciting checkpoint signalling and recruitment of downstream repair factors like the Fanconi anaemia FANCI:FANCD2 complex. Accordingly, FANCM deficiency causes chromosome fragility and cancer susceptibility. Other recent advances link FANCM to roles in gene editing efficiency and meiotic recombination, along with emerging synthetic lethal relationships, and targeting opportunities in ALT-positive cancers. Here we review key properties of FANCM's biochemical activities, with a particular focus on branchpoint translocation as a distinguishing characteristic.