Figure 1.

Summary of the activity of FANC proteins in the FA/BRCA pathway. The main function of this pathway is the removal of DNA interstrand crosslink (ICL); 22 FANC proteins participate in: (1) Lesion recognition. FANCM and its partners recognize ICLs during the convergence of two replication forks and promote ATR activation; the CMG helicase complex is unloaded to allow the approach of the leading strands to the ICL. (2) FA core complex recruitment. FANCM and its partners recruit the FA core complex and UBE2T/FANCT (the “upstream” proteins), to exert their E3-ubiquitin ligase activity and monoubiquitinate the FANCI and FANCD2 heterodimer (also known as the “ID2 or central complex”). (3) ID2 complex monoubiquitination. The monoubiquitinated central complex activates the endonucleolytic function of FANCP-SLX4-FANCQ/XPF resulting in the unhooking of the ICL from one of the DNA strands and the generation of a DSB. Both DNA ends of the DSB are processed by the MRN/CtIP complex to form a 3′ overhang. In the opposite strand, the unhooked ICL has now become an adduct; to bypass it, the REV1-polymerase ζ complex (including FANCV protein) performs translesion synthesis of the new strand. (4) The processed DSB is repaired by homologous recombination. The “downstream” FANCD1/BRCA2, FANCN/PALB2, FANCS/BRCA1, FANCJ/BRIP1, FANCO/RAD51C and FANCR/RAD51 proteins coordinate to coat the processed DNA strand of the DSB with RAD51/FANCR and paralogs RAD51C/FANCO, to invade the newly polymerase ζ-synthesized double strand of its sister chromatid, using it as a template to recover the original nucleotide sequence. (5) The cycle finishes with deubiquitination and unloading of the ID2 complex by USP1-UAF1 and the removal of the ICL-adduct by NER (nucleotide excision repair) pathway [9,12,22,23,24].