GENETIC CONTROL OF NUTRITIONAL STARVATION IN YEAST

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Experiments are designed to determine the mechanism by which gene expression is controlled by ploidy in the yeast Saccharomyces cerevisiae. This work has implications for abnormal cell growth in humans because tumor cells with aberrant cell control often contain an abnormal number of chromosomes. Although hyperploidy is usually viewed as a consequence of aberrant cell cycle control, this proposal suggests that hyperploidy itself may cause the abnormal expression of key molecules required for cell proliferation. Gene arrays will be used to determine the molecular basis for the ploidy control of gene transcription in isogenic yeast strains whose ploidy varies from haploid to tetraploid. One set of experiments is designed to identify the role of G1 cyclin transcription in the ploidy control of cell size and cell proliferation. These studies will determine whether ploidy control is itself cell cycle regulated. As polyploid cells are much more sensitive to nutritional starvation that their euploid counterparts, the genes responsible for the differences in euploid and polyploid growth control will be identified. The role of heterozygosity at the mating type locus and chromosome pairing in the response of polyploids to nutritional starvation will be ascertained. The promoter of one of the genes known to be transcriptionally controlled by ploidy will be analyzed to identify cis-acting sequences that respond to ploidy control. Another screen is designed to identify the trans-acting genes that mediate ploidy control. Salt resistance, a ploidy sensitive phenotype, will be used to screen for suppressors of the ploidy dependent phenotype. In addition the cellular basis for salt sensitivity will be elucidated. A third set of experiments identifies the role of the Rim1 transcription factor in stationary phase metabolism. This yeast homolog of a known fungal regulator of penicillin production is proposed to control stationary phase metabolism in Saccharomyces. A fourth set of experiments focuses on the role of dipthamide, a conserved posttranslational modification of elongation factor2 in cellular regulation. dph mutants have a stationary phase defect that is again more severe in diploids that in haploids. The experiments proposed will lead to a deeper understanding of the role of ploidy in aberrant cell proliferation.