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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.
Highlights
Hydrogen selenide, produced by the reduction of inorganic selenium salts, is believed to exert a key role in the toxicity as well as in the anticarcinogenic properties of selenium[13]
Seitomer et al.[16] showed that tolerance to SeMet treatment was largely unaffected by the loss of most of the genes involved in DNA damage and oxidative stress pathways, suggesting that SeMet toxicity involves mechanisms distinct from those of inorganic selenium
To identify cellular targets of SeMet in S. cerevisiae, we screened a collection of ≈4 900 isogenic haploid non-essential deletion mutants and ≈1000 haploid DAmP (Decreased Abundance by mRNA Perturbation) mutants of essential genes, by growth in liquid culture of pooled bar-coded mutants
Summary
Hydrogen selenide, produced by the reduction of inorganic selenium salts (selenate, selenite), is believed to exert a key role in the toxicity as well as in the anticarcinogenic properties of selenium[13] It reacts with dioxygen and thiols, resulting in the generation of ROS that induce oxidative stress, DNA damage and, cell death[14]. The origin of the toxicity of these metabolites remained unknown To address this question, we have screened the systematic collection of S. cerevisiae haploid knockout strains, previously used to determine biological processes involved in sensitivity to sodium selenide[15], to analyze the effects of loss of function on growth in the presence of SeMet. To address this question, we have screened the systematic collection of S. cerevisiae haploid knockout strains, previously used to determine biological processes involved in sensitivity to sodium selenide[15], to analyze the effects of loss of function on growth in the presence of SeMet This analysis showed the importance of protein degradation pathways to protect cells against SeMet damages. Our results suggest that SeMet toxicity results from its metabolization into SeCys followed by random incorporation in the place of cysteine, which in turn promotes protein aggregation
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