A Molecular, Genetic, and Diagnostic Spotlight on Fanconi Anemia

Figure 1

Schematic overview of the FA pathway. The FA pathway operates to maintain genomic stability in response to stalled replication forks, particularly in the context of interstrand DNA crosslinks (ICLs) that covalently link the two strands of the DNA helix. Replication stalling is detected by the FANCM sensor complex and triggers the activation of the Rad3-related protein kinase ATR, resulting in the phosphorylation of several FA proteins. FANCM becomes a docking platform for the other FA core complex proteins including the FANCL E3 ubiquitin ligase. The core complex activates the two members of the ID complex, FANCD2 and FANCI, by monoubiquitination (Ub) to promote ICL repair. The incision complex includes FANCP/SLX and ERCC1 and is essential to resolve the crosslink. Repair and replication fork restart is further accomplished using translesion synthesis (TLS) and homology-directed repair (HDR) which involves BRCA2/FANCD1, PALB2/FANCN, and RAD51C/FANCO.