Figure 1

Current model of the Fanconi anemia pathway. (Adapted with modifications from “The molecular pathogenesis of Fanconi anemia: recent progress” Taniguchi T and D'Andrea AD. Blood, Jun 2006; 107: 4223 – 4233. [6]) Eight FA proteins (FANC-A, -B, -C, -E, -F, -G, -L and -M), a FANCM-interacting protein called FAAP24 and an unidentified factor (FAAP100) form a nuclear complex (the FA core complex) with E3 ubiquitin ligase activity. FANCL is the catalytic subunit of the complex and directly interacts with the E2 ubiquitin conjugating enzyme UBE2T through its PHD/RING domain. UBE2T can be inactivated by auto-monoubiquitylation on lysine 91 (K91), but is suggested to form a thioester intermediate with ubiquitin through it's catalytic cysteine 86 (C86) when taking part in the ubiquitylation of FANCD2 (see below). The FA core complex, BLM, RPA and topoisomerase IIIα form a larger super-complex called BRAFT. Note that for diagrammatic purposes the FA core complex is shown here interacting with the FAAP100 subunit, but in reality the quaternary structure of the BRAFT complex is unknown. In response to exogenous DNA damage, or during normal S phase progression, the FANCD2 protein is monoubiquitylated on lysine 561 (K561) in an FA core complex- and UBE2T-dependent manner. DNA damage-induced monoubiquitylation of FANCD2 also requires ATR and RPA. Monoubiquitylation of FANCD2 targets the protein into nuclear foci where it co-localizes with BRCA1, FANCD1/BRCA2, FANCN/PALB2, RAD51, FANCJ/BRIP1 and other proteins. At least some components of the FA core complex (FANCC, FANCE and FANCG) also form nuclear foci. All of these factors are required for cellular resistance to DNA crosslinking agents. Monoubiquitylation of PCNA on lysine 164 (K164) requires RAD6 as an E2 and RAD18 as an E3, but not the FA core complex. In turn, modification of PCNA causes recruitment of translesion synthesis (TLS) DNA polymerases at the site of stalled replication forks. USP1 deubiquitylates both PCNA and FANCD2, negatively regulating both the Fanconi anemia pathway and monoubiquitylation of PCNA.