Analysis of <i>Saccharomyces cerevisiae </i>null allele strains identifies a larger role for DNA damage <i>versus</i> oxidative stress pathways in growth inhibition by selenium

Seitomer, Eden; Balar, Bharvi; He, Dongming; Copeland, Paul R.; Kinzy, Terri Goss

doi:10.1002/mnfr.200700347

Cited by 29 publications

(31 citation statements)

References 48 publications

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“…In vitro, oxidation of selenide by O 2 produces ROS including hydroxyl radicals ( ⅐ OH) (11)(12)(13). These species cause cellular alterations, in particular DNA damage, as evidenced by the importance of DNA repair systems in the resistance to selenite or selenide exposure (13)(14)(15)(16)(17)(18). Involvement of the GSH redox pathway was also demonstrated, indicating that selenite and selenide cause an oxidative stress in vivo (19 -21).…”

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confidence: 99%

Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae*

Lazard

Dauplais

Blanquet

et al. 2015

Journal of Biological Chemistry

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Background:The mechanisms underlying selenomethionine toxicity are poorly understood. Results: Saccharomyces cerevisiae mutations affecting sulfur metabolism or superoxide degradation impact selenomethionine toxicity. Conclusion: Selenomethionine primarily exerts its toxicity via the seleno-amino acids selenohomocysteine and selenocysteine. Significance: This study highlights the as yet underestimated importance of the trans-sulfuration pathway in selenomethionine toxicity.

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confidence: 99%

Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae*

Lazard

Dauplais

Blanquet

et al. 2015

Journal of Biological Chemistry

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“…PTC2 overexpression confers sensitivity to genotoxic agents such as hydroxyurea or UV radiation (63) and allows growth of strains carrying a dominant lethal allele of Rad53. Similarly, ptc2 mutants are sensitive to selenite, a compound that induces DNA damage, probably by inducing double-strand break (86). It has been proposed that both Ptc2 and Ptc3 are necessary for the inactivation of Rad53 by dephosphorylation after a doublestrand break of DNA induced by HO endonuclease (50), although there is no evidence for a direct in vitro effect.…”

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confidence: 99%

Type 2C Protein Phosphatases in Fungi

2011

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Type 2C Ser/Thr phosphatases are a remarkable class of protein phosphatases, which are conserved in eukaryotes and involved in a large variety of functional processes. Unlike in other Ser/Thr phosphatases, the catalytic polypeptide is not usually associated with regulatory subunits, and functional specificity is achieved by encoding multiple isoforms. For fungi, most information comes from the study of type 2C protein phosphatase (PP2C) enzymes in Saccharomyces cerevisiae, where seven PP2C-encoding genes (PTC1 to -7) with diverse functions can be found. More recently, data on several Candida albicans PP2C proteins became available, suggesting that some of them can be involved in virulence. In this work we review the available literature on fungal PP2Cs and explore sequence databases to provide a comprehensive overview of these enzymes in fungi.Reversible phosphorylation of proteins is a major mechanism regulating many biological processes such as metabolism, gene transcription, or cell cycle. It is an extremely common event in signal transduction, and it is considered the main mechanism of posttranslational modification leading, for instance, to a change in enzyme activity. The phosphorylation state of a protein results from the balance of protein kinases and protein phosphatases activities. Alterations in the phosphorylation state of proteins are a cause of various diseases, such as cancer, diabetes, rheumatoid arthritis, or hypertension. The importance of this regulatory mechanism is evident when it is considered that it affects around 30% of the proteome of Saccharomyces cerevisiae (72) and that the number of genes encoding phosphatases and kinases represents 2 to 4% of all genes in a typical eukaryotic genome (60).Most phosphorylation events in eukaryotes involve transfer of phosphate to Ser and Thr residues. Removal of this phosphate is catalyzed by Ser/Thr protein phosphatases. Members of this large family of enzymes were initially classified, using enzymological criteria, as type 1 (PP1) and type 2 (PP2) phosphatases. PP2 enzymes were subsequently divided into three groups on the basis of the requirements for metal ions: 2A (not requiring metal ions), 2B (activated by calcium), and 2C (Mg 2ϩ dependent) (10). The molecular cloning of a number of cDNAs and genes from diverse organisms allowed the establishment of three major subfamilies: PPP (phosphoprotein phosphatases), including type 1, 2A, and 2B phosphatases, among others; PPM (metal-dependent protein phosphatases), including type 2C enzymes (PP2C), which are the subject of this review; and the catalytically Asp-based subfamily, represented by HAD and FCP/SCP (see reference 89 for a review).Although PP2C proteins are distantly related in primary sequence to PPP enzymes, their tridimensional structure and catalytic mechanisms appear to be quite similar. Type 2C phosphatases are widely represented in bacteria, fungi, plants, insects, and mammals (83), suggesting that they are involved in key cellular processes, such as proliferation, metabolism, and cell...

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“…Comparison of the effects of SeMet and selenite on the growth of wild-type and mutant yeast cells indicated the lesser importance of DNA damage in SeMet vs. selenite toxicity (91). Likewise, SeMet treatment did not result in DNA damage in human lymphocytes, even at cytotoxic concentrations (136).…”

Section: Selenomethionine Toxicitymentioning

confidence: 98%

Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

Lazard

Dauplais

Blanquet

et al. 2017

Biomolecular Concepts

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Selenium is an essential trace element due to its incorporation into selenoproteins with important biological functions. However, at high doses it is toxic. Selenium toxicity is generally attributed to the induction of oxidative stress. However, it has become apparent that the mode of action of seleno-compounds varies, depending on its chemical form and speciation. Recent studies in various eukaryotic systems, in particular the model organism Saccharomyces cerevisiae, provide new insights on the cytotoxic mechanisms of selenomethionine and selenocysteine. This review first summarizes current knowledge on reactive oxygen species (ROS)-induced genotoxicity of inorganic selenium species. Then, we discuss recent advances on our understanding of the molecular mechanisms of selenocysteine and selenomethionine cytotoxicity. We present evidences indicating that both oxidative stress and ROSindependent mechanisms contribute to selenoamino acids cytotoxicity. These latter mechanisms include disruption of protein homeostasis by selenocysteine misincorporation in proteins and/or reaction of selenols with protein thiols.

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Analysis of Saccharomyces cerevisiae null allele strains identifies a larger role for DNA damage versus oxidative stress pathways in growth inhibition by selenium

Cited by 29 publications

References 48 publications

Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae*

Trans-sulfuration Pathway Seleno-amino Acids Are Mediators of Selenomethionine Toxicity in Saccharomyces cerevisiae*

Type 2C Protein Phosphatases in Fungi

Recent advances in the mechanism of selenoamino acids toxicity in eukaryotic cells

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