MODEL STUDIES OF THE FANCONI/BRCA/RECOMBINATION PATHWAY

The Fanconi Anaemia syndrome is a rare hereditary disease caused by mutations in at least eight genes. These genes code for proteins that interact with each other and eventually regulate the FANCD2 protein activity. Being the last ring of this chain of events, it is likely that this protein is the one responsible of the pathology in all the Fanconi Anaemia cases. This protein appears to be involved in DNA damage repair. When both the DNA strands are interrupted, the only kind of repair, allowing recover of the DNA information and therefore of the normal cell function, is the repair by homologous recombination. The same battery of genes involved in this mechanism is responsible of the exchange of information during the gametogenesis; in this case the recombination is physiologic and essential for fertility. The Fanconi anaemia patients show a large spectrum of symptoms (among which predisposition to cancer and poor fertility) explainable on the whole by the incapacity of DNA damage repair. The pathology is so complex in its manifestations that the diagnosis and the therapy are often delayed and therefore ineffectual. We have a detailed knowledge of the battery of genes involved in recombination in one of the most useful model organisms for these kinds of studies: the nematode C. elegans that has already been shown useful for the understanding of human pathologies (in fact the Nobel Prize for Medicine 2002 has been assigned because of researches in this nematode).Proteins involved in homologous recombination, as well as FANCD2, are conserved in evolution. We will use our expertise to understand the function of this protein and the deleterious effects of its absence or malfunctioning, and to identify other proteins that act synergistically or antagonistically. These advances in knowledge will make the diagnosis more accurate and will indicate new targets for pharmacologic and gene therapy.