FANCM

FANCM is a large (~250 kDa) DEAH-box family DNA-dependent ATPase and ATP-dependent DNA translocase that acts at stalled replication forks and DNA interstrand crosslinks (ICLs) to maintain genome stability. It is the most conserved Fanconi anemia protein, orthologous to archaeal Hef and to yeast Mph1/Fml1. Its N-terminal SF2 helicase/translocase domain (Walker A ATP-binding site, catalytic Lys117) uses ATP hydrolysis to translocate on duplex DNA and to catalyze branch migration of replication forks and Holliday junctions, thereby remodeling branched replication/recombination intermediates. Its catalytically dead C-terminal ERCC4/XPF-like domain heterodimerizes with FAAP24, and a central region binds the MHF1-MHF2 histone-fold dimer (CENPS-CENPX); the MHF dimer stimulates FANCM DNA binding and fork remodeling. Through these interactions FANCM anchors the Fanconi anemia core complex to chromatin at sites of replication stress, which is required for efficient DNA damage-induced monoubiquitination of the FANCD2-FANCI complex and for ATR checkpoint signaling. FANCM also promotes replication traverse of ICLs and suppresses sister-chromatid exchange and crossover recombination, acting as a regulator of homologous recombination rather than a core HR enzyme. The protein is nuclear and chromatin-bound, becomes hyperphosphorylated in response to genotoxic stress, and is highly expressed in germ cells; biallelic loss-of-function causes spermatogenic failure and premature ovarian failure.

Disorders

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