Yeast mutants as a model system for identification of determinants of chemosensitivity

The fission yeast Schizosaccharomyces pombe and the budding yeast Saccharom yces cerevisiae have become valuable tools for the study of basic cellular functions of eukaryotic cells, including DNA repair mechanisms and cell cyc le control. Since the major signaling pathways and cellular processes invol ved in cellular response to cytotoxic agents are conserved between yeasts a nd mammalian cells, these simple eukaryotic systems could be excellent mode ls for the identification of molecular/cellular mechanisms of sensitivity t o antitumor drugs. We describe relevant biological features of yeast cells and potential applications derived by their genetic manipulation. In partic ular, we have outlined the role of genes involved in repair processes and i n checkpoint control, with specific reference to genes regulating radiation -sensitivity. Specific examples are provided concerning the use of both yea sts in understanding the mechanism of action of platinum compounds and topo isomerase inhibitors. The availability of the genomic sequence of these org anisms as well as of new technologies (microarrays, proteomics) is expected to allow the identification of potential drug targets, since the drug disc overy process is moving toward a genomic orientation. Among eukaryotic orga nisms, yeasts are suitable for easy genetic manipulations, and specific gen etic alterations are exploitable for assessing the effects of chemotherapeu tic agents with different mechanism of action. Although still at an early s tage, this fast-moving field shows promise as a novel and potentially usefu l method for development of target-specific therapeutic approaches.