title: Ribosome quality control is a central protection mechanism for yeast exposed to deoxynivalenol and trichothecin.
abstract: The trichothecene mycotoxins deoxynivalenol (DON) and trichothecin (TTC) are inhibitors of eukaryotic protein synthesis. Their effect on cellular homeostasis is poorly understood. We report a systematic functional investigation of the effect of DON and TTC on the yeast Saccharomyces cerevisiae using genetic array, network and microarray analysis. To focus the genetic analysis on intracellular consequences of toxin action we eliminated the PDR5 gene coding for a potent pleiotropic drug efflux protein potentially confounding results. We therefore used a knockout library with a pdr5Δ strain background.
  
  
  
  DON or TTC treatment creates a fitness bottleneck connected to ribosome efficiency. Genes isolated by systematic genetic array analysis as contributing to toxin resistance function in ribosome quality control, translation fidelity, and in transcription. Mutants in the E3 ligase Hel2, involved in ribosome quality control, and several members of the Rpd3 histone deacetylase complex were highly sensitive to DON. DON and TTC have similar genetic profiles despite their different toxic potency. Network analysis shows a coherent and tight network of genetic interactions among the DON and TTC resistance conferring gene products. The networks exhibited topological properties commonly associated with efficient processing of information. Many sensitive mutants have a "slow growth" gene expression signature. DON-exposed yeast cells increase transcripts of ribosomal protein and histone genes indicating an internal signal for growth enhancement.
  
  
  
  The combination of gene expression profiling and analysis of mutants reveals cellular pathways which become bottlenecks under DON and TTC stress. These are generally directly or indirectly connected to ribosome biosynthesis such as the general secretory pathway, cytoskeleton, cell cycle delay, ribosome synthesis and translation quality control. Gene expression profiling points to an increased demand of ribosomal components and does not reveal activation of stress pathways. Our analysis highlights ribosome quality control and a contribution of a histone deacetylase complex as main sources of resistance against DON and TTC.
authors.affiliation: Plant Genome and Systems Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Kugler
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria.
authors.forename: Zeljkica
authors.initials: Z
authors.lastname: Jandric
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Beyer
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Klopf
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Glaser
authors.affiliation: University of Natural Resources and Life Sciences, Vienna (BOKU), Institute for Biotechnology in Plant Production, Konrad-Lorenz-Straße 20, 3430, Tulln an der Donau, Austria.
authors.forename: Marc
authors.initials: M
authors.lastname: Lemmens
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shams
authors.affiliation: Plant Genome and Systems Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Neuherberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mayer
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Adam
authors.affiliation: Department of Applied Genetics and Cell Biology, UFT-Campus Tulln-Konrad, University of Natural Resources and Life Sciences, Vienna (BOKU), Konrad Lorenz Strasse 24, 3430, Tulln an der Donau, Austria. Christoph.Schueller@boku.ac.at.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schüller
mesh_terms: D042002:Chromatin Assembly and Disassembly; D016000:Cluster Analysis; D025141:Drug Resistance, Fungal; D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D005800:Genes, Fungal; D006657:Histones / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D012270:Ribosomes / Q000378:metabolism*; D014255:Trichothecenes / Q000494:pharmacology*; D015003:Yeasts / Q000187:drug effects* / Q000502:physiology*
chemical_list: D006657:Histones; D014255:Trichothecenes; C025711:trichothecin; C007262:deoxynivalenol
keywords: Deoxynivalenol; Fusarium; Mycotoxins; RSC complex; Ribosome; Synthetic genetic array; Translation quality control; Trichothecenes; Yeast