The Fanconi anaemia/BRCA pathway

Abstract
Fanconi anaemia (FA) is an autosomal recessive disease that is characterized by developmental abnormalities, cancer susceptibility and cellular sensitivity to crosslinking agents. The seven cloned FA proteins interact in a common pathway. Five FA proteins (A, C, E, F and G) regulate the activation, via monoubiquitylation, of FANCD2. Activated FANCD2 is targeted to BRCA1 nuclear foci. The FANCD1 gene is BRCA2. The FA/BRCA pathway seems to regulate DNA repair by homologous recombination. Ionizing radiation activates the ATM-dependent phosphorylation of FANCD2, resulting in an intra-S checkpoint response. FANCD2 interacts with the MRE11–NBS1–RAD50 complex in the repair of DNA crosslinks. Somatic inactivation of the FA/BRCA pathway accounts for the chromosomal instability of some cancers in the general population. Mouse models for FA subtypes A, C, D1, D2 and G have been generated. DNA crosslink repair, which is defective in cells from FA patients, requires S-phase arrest and homologous recombination repair.