Fig. 2

FA/BRCA pathway and crosstalk between FA and other DNA repair pathways. In response to upstream DNA damage signaling (such as phosphorylation by ATR/ATM), in the FA/BRCA pathway [1], the FA core complex forms––comprising FANCA (A), FANCB (B), FANCC (C), FANCE (E), FANCF (F), FANCG (G), FANCM (M), and FANCL (L) proteins, plus FAAP20, FAAP24, and FAAP100 (FAAP). This core complex binds UBE2T(T) via FANCL, which then activates FANCD2/I dimers through mono-ubiquitination. The activated FANCD2/I (D2/I) complex then translocates to DNA - damage sites and recruits downstream FA effector proteins––including BRCA1 (S), BRCA2 (D1), RAD51 (R), BRIP1 (J), PALB2 (N), RAD51C (O), SLX4 (P), and ERCC4 (Q), plus other DNA repair molecules (such as FAN1) to the lesion site to repair damage. In the FANCM/BS pathway [2], the FA core complex binds to the BS complex by way of interactions between FANCM-RMI1 and TopoIIIα of the BS complex and translocates to the lesion site. In the FANCD2/ATM pathway [3], in response to ionizing radiation or ICL-inducing agents, FANCD2 is phosphorylated by ATM and co-localizes with the NMR complex to repair DNA damage or cause S-phase arrest. ICL interstrand cross-links, ATR ataxia-telangiectasia-Ser/Thr-protein kinase, ATM ataxia telangiectasia mutated kinase, FAAP FA-associated proteins, FAN1 FA-associated nuclease-1, BS Bloom’s syndrome protein, RMI1/2 RecQ-mediated genomic instability protein 1/2, TopoIIIα topoisomerase IIIα, NMR the NBS1/MRE11/RAD50 complex