Regulation of an IMP dehydrogenase gene and its overexpression in drug-sensitive transcription elongation mutants of yeast

IMP dehydrogenase is a rate-limiting enzyme involved in the synthesis of GT P. In mammalian cells it is regulated with respect to growth rate and is th e target of numerous therapeutic agents. Mutations in the RNA polymerase II elongation machinery render yeast sensitive to inhibitors of IMP dehydroge nase and defective in inducing transcription of one of the IMP dehydrogenas e-encoding genes, IMD2. Here we show that loss of IMD2, but not IMD1, IMD3, or IMD4, conferred upon yeast the same drug sensitivity found in elongatio n mutants. We tested whether the drug sensitivity of elongation mutants is due to their inability to induce IMD2 by providing them with exogenous copi es of the gene. In some elongation mutants, overexpression reversed drug se nsitivity and a transcriptional defect. Overexpression in mutants with a mo re severe phenotype partially suppressed drug sensitivity but was inconsequ ential in reversing a defect in transcription. These findings suggest that the drug sensitivity of elongation mutants is largely but not solely attrib utable to defects in the ability to induce IMD2, because transcription is c ompromised even when IMD2 mRNA levels are adequate. We describe two DNA seq uence elements in the promoter of the gene that regulate it. We also found that IMD2 mRNA abundance is coupled to cell growth rate. These findings sho w that yeast possess a conserved system that gauges nucleotide pools and ce ll growth rate and responds through a uniquely regulated member of the IMD gene family.