The Fanconi Anemia/BRCA Pathway

Studies on cancer-prone and rare human genetic disorders often lead to significant advances in our understanding of the complex network of genome stability and DNA repair pathways that have evolved in the human genome to prevent the harmful effects of exposure to DNA damaging agents. One such disorder is Fanconi Anemia, an autosomal recessive disease characterized by an increased spontaneous and DNA cross-linkers induced chromosome instability, progressive pancytopenia and cancer susceptibility. At least eleven genes are involved in Fanconi anemia, including the breast cancer susceptibility gene BRCA2. Six of the Fanconi anemia proteins (FANCA, C, E, F, G and L) assemble in a complex that is required for FANCD2 activation by monoubiquitination in response to DNA damage or during S-phase progression. Active FANCD2 then colocalizes with the product of the breast cancer susceptibility gene BRCA1 in discrete nuclear foci. FANCD2 is also independently phosphorylated by ATM in response to ionising radiation and interacts with the MRE1 l/Rad50/NBSl complex, which is directly involved in homologous recombination DNA repair pathway and in cell cycle checkpoint response to DNA damage. Available data indicate that FANCD2 is involved in cell cycle regulation and DNA repair. Our current knowledge on the functional significance of FA pathway and more specifically FANCD2 and its interacting proteins in pathways of genomic surveillance and maintenance will be discussed in this chapter.