FANCMs

FANCM proteins are large, nuclear DNA translocases that function as part of the Fanconi anemia (FA) DNA repair pathway. Named for the Fanconi anemia complementation group M, FANCM proteins are conserved across eukaryotes and play a central role in maintaining genome stability during DNA replication and in response to DNA crosslinking damage. In humans, the gene FANCM encodes the core FANCM protein; homologs exist in plants, fungi, and other animals.

Functionally, FANCMs recognize branched DNA structures, such as stalled replication forks, and use ATP hydrolysis to remodel DNA. This activity helps stabilize forks, promotes fork restart, and coordinates the processing of DNA interstrand crosslinks with other FA components. FANCM also participates in the signaling events that activate the FA pathway, facilitating interactions with the FA core complex and with FANCD2/FANCI at damage sites, often in conjunction with MHF1/2 histone-fold proteins and FAAP24 to form a repair module.

Structurally, FANCM proteins contain an N-terminal ATPase/helicase-like domain of the SF2 family and a C-terminal region that mediates interactions with FA components and MHF. The ATPase activity is essential for its translocase function, and conserved motifs such as Walker A and B drive ATP binding and hydrolysis. This modular architecture supports both DNA remodeling and recruitment of repair factors to sites of replication stress.

Evolution and clinical relevance: FANCM homologs are present in diverse organisms, and loss of FANCM-like activity increases sensitivity to DNA crosslinking agents and replication stress. In humans, rare germline variants in FANCM have been linked to Fanconi anemia in some cases, and somatic alterations have been observed in cancer, influencing DNA damage responses and therapeutic sensitivity. Ongoing research seeks to delineate the full interaction network and regulatory mechanisms of FANCMs within the FA pathway.