Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway

Fanconi anaemia (FA) is an autosomal recessive inherited disorder associate d with a progressive aplastic anaemia, diverse congenital abnormalities and cancer. The condition is genetically heterogeneous, with at least seven co mplementation groups (A-G) described. Cells from individuals who are homozy gous for mutations in FA genes are characterized by chromosomal instability and hypersensitivity to DNA interstrand crosslinking agents, These feature s suggest a possible role for the encoded proteins in the recognition or re pair of these lesions, but neither their function nor whether they operate in a concerted or discrete functional pathways is known. The recent cloning of the FANCF and FANCE genes has allowed us to investigate the interaction of the proteins encoded by five of the seven complementation groups of FA, We used the yeast two-hybrid system and co-immunoprecipitation analysis to test the 10 possible pairs of proteins for direct interaction. In addition to the previously described binding of FANCA to FANCG, we now demonstrate direct interaction of FANCF with FANCG, of FANCC with FANCE and a weaker in teraction of FANCE with both FANCA and FANCG, These findings show that the newly identified FANCE protein is an integral part of the FA pathway, and s upport the concept of a functional link between all known proteins encoded by the genes that are mutated in this disorder. These proteins may act eith er as a multimeric complex or by sequential recruitment of subsets of the p roteins in a common pathway that protects the genomic integrity of mammalia n cells.