Model for the role of FANCM in regulating the FA pathway. (A) HeLa cells silenced for the indicated proteins by siRNA (columns) were analyzed for MMC sensitivity, FANCD2 monoubiquitination, presence of FA core complex, and chromatin localization of FA core complex (rows). + indicates indistinguishable from control siRNA–treated cells; and −, defective. (B) Schematic model describing the function of FANCM in the chromatin recruitment of the FA core complex. The FANCM-FAAP24 complex associates with chromatin throughout the cell cycle. Early in the cell cycle (G₁ phase), the FA core (A/B/C/E/F/G/L complex) is assembled but does not associate with FANCM-FAAP24 complex in chromatin. In S phase, phosphorylated FANCM can recruit the FA core complex to chromatin, possibly to replication forks, and induce E3 ubiquitin ligase activity, resulting in monoubiquitination of FANCD2 and FANCI. In G₂/M phase, hyperphosphorylated FANCM may promote the release of the FA core complex, and USP1 may deubiquitinate FANCD2 and FANCI monoubiquitination.