title: Exposure to selenomethionine causes selenocysteine misincorporation and protein aggregation in Saccharomyces cerevisiae.
abstract: Selenomethionine, a dietary supplement with beneficial health effects, becomes toxic if taken in excess. To gain insight into the mechanisms of action of selenomethionine, we screened a collection of ≈5900 Saccharomyces cerevisiae mutants for sensitivity or resistance to growth-limiting amounts of the compound. Genes involved in protein degradation and synthesis were enriched in the obtained datasets, suggesting that selenomethionine causes a proteotoxic stress. We demonstrate that selenomethionine induces an accumulation of protein aggregates by a mechanism that requires de novo protein synthesis. Reduction of translation rates was accompanied by a decrease of protein aggregation and of selenomethionine toxicity. Protein aggregation was supressed in a ∆cys3 mutant unable to synthetize selenocysteine, suggesting that aggregation results from the metabolization of selenomethionine to selenocysteine followed by translational incorporation in the place of cysteine. In support of this mechanism, we were able to detect random substitutions of cysteinyl residues by selenocysteine in a reporter protein. Our results reveal a novel mechanism of toxicity that may have implications in higher eukaryotes.
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Plateau
authors.affiliation: Institut Pasteur, Unité de Génétique des Interactions Macromoléculaires, CNRS-UMR3525, Paris, France.
authors.forename: Cosmin
authors.initials: C
authors.lastname: Saveanu
authors.affiliation: Laboratoire d'Optique et Biosciences, Ecole Polytechnique, CNRS UMR7645-INSERM U1182 91128, Palaiseau Cedex, France.
authors.forename: Roxane
authors.initials: R
authors.lastname: Lestini
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Dauplais
authors.affiliation: Institut Pasteur, Unité de Génétique des Interactions Macromoléculaires, CNRS-UMR3525, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Decourty
authors.affiliation: Institut Pasteur, Unité de Génétique des Interactions Macromoléculaires, CNRS-UMR3525, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Jacquier
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Blanquet
authors.affiliation: Laboratoire de Biochimie, Ecole Polytechnique, CNRS UMR7654, 91128 Palaiseau Cedex, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Lazard
mesh_terms: D000595:Amino Acid Sequence; D019992:Databases as Topic; D017353:Gene Deletion; D063990:Gene Ontology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D066329:Protein Aggregates; D015203:Reproducibility of Results; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017279:Selenocysteine / Q000378:metabolism*; D012645:Selenomethionine / Q000633:toxicity*
chemical_list: D010455:Peptides; D066329:Protein Aggregates; D029701:Saccharomyces cerevisiae Proteins; D017279:Selenocysteine; D012645:Selenomethionine