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Repression of pleiotrophic drug resistance genes in Saccharomyces cerevisiae using chimeric transcriptional repressors

ABSTRACT: Yeast is a powerful model system for studying the action of small molecule therapeutics. An important limitation has been low efficacy of many small molecules in yeast due to limited intracellular drug accumulation. We used the DNA binding domain of the pleiotropic drug resistance regulator Pdr1 fused in-frame to transcription repressors to repress Pdr1 regulated genes. Expression of these regulators conferred dominant enhancement of drug sensitivity and led to greatly diminished levels of Pdr1p regulated transcripts, including the yeast p-glycoprotein homologue Pdr5. Enhanced sensitivity was seen for a wide range of small molecules. Biochemical measurements demonstrated enhanced accumulation of rhodamine in yeast cells carrying the chimeras. These repressors of Pdr1p regulated transcripts can be introduced into large collections of strains such as the S. cerevisiae deletion set, and enhance the utility of yeast for studying drug action and for mechanism-based drug discovery. Keywords: Comparison of genetic variants

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE8326 | GEO | 2007/06/29

SECONDARY ACCESSION(S): PRJNA101315

REPOSITORIES: GEO

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Project description:The yeast Saccharomyces cerevisiae is able to adapt and in situ detoxify lignocellulose derived inhibitors such as furfural and HMF. The length of lag phase for cell growth in response to the inhibitor challenge has been used to measure tolerance of strain performance. Mechanisms of yeast tolerance at the genome level remain unknown. Using systems biology approache, this study investigated comparative transcriptome profiling, metabolic profiling, cell growth response and gene regulatory interactions of yeast strains and selective gene deletion mutations in response to HMF challenges during the lag phase of growth. Three hundred and sixty-five candidate genes were identified and found at least three significant components involving some of these genes that enable yeast adaptation and tolerance to HMF in yeast. First, functional enzyme coding genes such as ARI1, ADH6, ADH7 and OYE3, as well as gene interactions involved in the biotransformation and inhibitor detoxification were direct driving force to reduce HMF damages in cells. Expressions of these genes were regulated by YAP1 and its closely related regulons. Second, a large number of PDR genes, mainly regulated by PDR1 and PDR3, were induced during the lag phase and the PDR gene family-centered functions, including specific and multiple functions involving cellular transport such as TPO1, TPO4, RSB1, PDR5, PDR15, YOR1, and SNQ2, promoted cellular adaptation and survival in order to cope with the inhibitor stress. Third, expressed genes involving degradation of damaged proteins and protein modifications such as SHP1 and SSA4, regulated by RPN4, HSF1 and other co-regulators, were necessary for yeast cells to survive and adapt the HMF stress. A deletion mutation strainΔrpn4 was unable to recover the growth in the presence of HMF. Complex gene interactions and regulatory networks as well as co-regulations exist in yeast adaptation and tolerance to the lignocellulose derived inhibitor HMF. Both induced and repressed genes involving diversified functional categories are accountable for adaptation and energy rebalancing in yeast to survive and adapt the HMF stress during the lag phase of growth. Transcription factor genes YAP1, PDR1, PDR3, RPN4 and HSF1 appeared to play key regulatory rules for global adaptation in the yeast S. cerevisiae.

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Repression of pleiotrophic drug resistance genes in Saccharomyces cerevisiae using chimeric transcriptional repressors

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