Vol. 52, Issue 4, 477-492, December 2000

Yeast Mutants As a Model System for Identification of Determinants of Chemosensitivity

Paola Perego¹, Gretchen S. Jimenez, Laura Gatti, Stephen B. Howell and Franco Zunino

Istituto Nazionale Tumori, Milan, Italy (P.P., L.G., F.Z.); Vical Inc., San Diego, California (G.S.J.); and Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California (S.B.H.)

I. Introduction
II. Integrating Model Systems for Antitumor Pharmacology Studies
III. Relevant Features of Yeast Cells
IV. Use of Yeast Rad Mutants to Study Drug Mechanisms
V. Rationale for Using Yeast As a Model System
VI. Molecular Pathways Regulating DNA Damage Responses
    A. Checkpoint Control
    B. Nucleotide Excision Repair
    C. Recombinational Repair
    D. Additional Pathways
VII. Conclusions
Acknowledgments
References

The fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae have become valuable tools for the study of basic cellular functions of eukaryotic cells, including DNA repair mechanisms and cell cycle control. Since the major signaling pathways and cellular processes involved in cellular response to cytotoxic agents are conserved between yeasts and mammalian cells, these simple eukaryotic systems could be excellent models for the identification of molecular/cellular mechanisms of sensitivity to antitumor drugs. We describe relevant biological features of yeast cells and potential applications derived by their genetic manipulation. In particular, we have outlined the role of genes involved in repair processes and in checkpoint control, with specific reference to genes regulating radiation-sensitivity. Specific examples are provided concerning the use of both yeasts in understanding the mechanism of action of platinum compounds and topoisomerase inhibitors. The availability of the genomic sequence of these organisms as well as of new technologies (microarrays, proteomics) is expected to allow the identification of potential drug targets, since the drug discovery process is moving toward a genomic orientation. Among eukaryotic organisms, yeasts are suitable for easy genetic manipulations, and specific genetic alterations are exploitable for assessing the effects of chemotherapeutic agents with different mechanism of action. Although still at an early stage, this fast-moving field shows promise as a novel and potentially useful method for development of target-specific therapeutic approaches.