title: Screening the yeast "disruptome" for mutants affecting resistance to the immunosuppressive drug, mycophenolic acid.
abstract: The immunosuppressive drug mycophenolic acid (MPA) is a potent and specific inhibitor of IMP dehydrogenase, the first committed step of GMP synthesis. A screen for yeast genes affecting MPA sensitivity, when overexpressed, allowed us to identify two genes, IMD2 and TPO1, encoding a homologue of IMP dehydrogenase and a vacuolar pump, respectively. In parallel, 4787 yeast strains, each carrying an identified knock-out mutation, were tested for growth in the presence of MPA, allowing identification of 100 new genes affecting MPA resistance when disrupted. Disturbance of several cellular processes, such as ergosterol biosynthesis, vacuole biogenesis, or glycosylation impaired the natural capacity of yeast to resist MPA, although most of the highly sensitive mutants affected the transcription machinery (19 mutants). Expression of TPO1 and/or IMD2 was strongly affected in 16 such transcription mutants suggesting that low expression of these genes could contribute to MPA sensitivity. Interestingly, the spt3, spt8, and spt20 mutants behaved differently than other Spt-Ada-Gcn5-acetyltransferase (SAGA) mutants. Indeed, in these three mutants, as in previously characterized transcription elongation mutants, IMD2 expression was only affected in the presence of MPA, thus suggesting a possible role for some SAGA subunits in transcription elongation.
authors.affiliation: Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, 1 rue Camille Saint-Saens, 33077 Bordeaux Cedex, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmoucelles
authors.forename: Benoit
authors.initials: B
authors.lastname: Pinson
authors.forename: Christelle
authors.initials: C
authors.lastname: Saint-Marc
authors.forename: Bertrand
authors.initials: B
authors.lastname: Daignan-Fornier
mesh_terms: D015152:Blotting, Northern; D004351:Drug Resistance / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008957:Models, Genetic; D009154:Mutation; D009173:Mycophenolic Acid / Q000494:pharmacology*; D016366:Open Reading Frames; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014158:Transcription, Genetic; D019076:Transgenes
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid