Genotoxicity of selenite in diploid yeast

Anjaria, K.B.; Madhvanath, U.

doi:10.1016/0165-1218(88)90063-8

Cited by 24 publications

(9 citation statements)

References 20 publications

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“…3). The selenite‐induced forward mutation frequency was found to be similar to the previously described induced back mutation frequency (Anjaria et al ., 1988). This mutagenic effect suggested that selenite led to damaged DNA, which could account for the observed arrest of treated cells.…”

Section: Resultsmentioning

confidence: 99%

“…To get an insight into these mechanisms, we have used yeast as a eukaryotic model organism to identify genes interfering with selenite toxicity. In this microorganism, selenite has a dual effect: in the micromolar range, selenite have been shown to inhibit spontaneous mutagenesis (Rosin, 1981); in the millimolar range, selenite becomes toxic and induces back-mutation, gene conversion and mitotic crossing-over (Anjaria and Madvanath, 1988). As a first step towards unravelling the molecular mechanisms leading to selenite toxicity and resistance, we have identified several yeast genes affecting resistance to selenite.…”

Section: Introductionmentioning

confidence: 99%

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Identification of genes affecting selenite toxicity and resistance in Saccharomyces cerevisiae

Pinson

Sagot

Daignan‐Fornier³

2000

Molecular Microbiology

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SummaryRecent studies associating dietary selenium with reduced cancer susceptibility have aroused interest in this substance. In the millimolar range, selenite is toxic and slightly mutagenic for yeast. We show that selenite-treated yeast cells tend to arrest as large budded cells and that this arrest is abolished in a rad9 mutant that is significantly sensitive to selenite. Interestingly, a rev3 mutant affected in the errorprone repair pathway is also sensitive to selenite, whereas mutations in the other DNA repair pathways do not strongly affect resistance to selenite. We propose that selenite treatment leads to DNA damage inducing the RAD9-dependent cell cycle arrest. Selenite-induced DNA damage could be converted to mutations by the Rev3p-dependent lesion bypass system, thus allowing the cell cycle to progress. We have also investigated the selenite detoxification mechanisms and identified three genes involved in this process. In the present study, we show that lack of the cadmium glutathione-conjugate vacuolar pump Ycf1p or overexpression of the sulphite resistance membrane protein Ssu1p enhance the capacity of yeast cells to resist selenite treatment. Finally, we show that overexpression of the glutathione reductase Glr1p increases resistance to selenite, suggesting that selenite toxicity in yeast is closely linked to its oxidative capacity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of genes affecting selenite toxicity and resistance in Saccharomyces cerevisiae

Pinson

Sagot

Daignan‐Fornier³

2000

Molecular Microbiology

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“…Moreover, ROS generated from the reaction of hydrogen selenide with molecular oxygen inside the cell (43) may also contribute to the oxidation of glutathione. Eventually, a decrease in the pool of intracellular reduced glutathione could yield an oxidative stress, thus possibly accounting for the genotoxic effects observed in yeast upon exposure to selenite or selenite:glutathione mixtures (14,15).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Production of Hydrogen Selenide Accounts for Thiol-assisted Toxicity of Selenite against Saccharomyces cerevisiae

Tarze¹,

Dauplais²,

Grigoras³

et al. 2007

Journal of Biological Chemistry

124

125

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Administration of selenium in humans has anticarcinogenic effects. However, the boundary between cancer-protecting and toxic levels of selenium is extremely narrow. The mechanisms of selenium toxicity need to be fully understood. In Saccharomyces cerevisiae, selenite in the millimolar range is well tolerated by cells. Here we show that the lethal dose of selenite is reduced to the micromolar range by the presence of thiols in the growth medium. Glutathione and selenite spontaneously react to produce several selenium-containing compounds (selenodiglutathione, glutathioselenol, hydrogen selenide, and elemental selenium) as well as reactive oxygen species. We studied which compounds in the reaction pathway between glutathione and sodium selenite are responsible for this toxicity. Involvement of selenodiglutathione, elemental selenium, or reactive oxygen species could be ruled out. In contrast, extracellular formation of hydrogen selenide can fully explain the exacerbation of selenite toxicity by thiols. Indeed, direct production of hydrogen selenide with D-cysteine desulfhydrase induces high mortality. Selenium uptake by S. cerevisiae is considerably enhanced in the presence of external thiols, most likely through internalization of hydrogen selenide. Finally, we discuss the possibility that selenium exerts its toxicity through consumption of intracellular reduced glutathione, thus leading to severe oxidative stress.

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“…All these studies indicate that selenite induces an oxidative stress in vivo . Other studies pinpoint involvement of selenium derivatives in genotoxic effects including base oxidations [15], [19], [20] and DNA breaks [15], [16], [21], [22].…”

Section: Introductionmentioning

confidence: 99%

Sodium Selenide Toxicity Is Mediated by O2-Dependent DNA Breaks

et al. 2012

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Hydrogen selenide is a recurrent metabolite of selenium compounds. However, few experiments studied the direct link between this toxic agent and cell death. To address this question, we first screened a systematic collection of Saccharomyces cerevisiae haploid knockout strains for sensitivity to sodium selenide, a donor for hydrogen selenide (H2Se/HSe−/Se2−). Among the genes whose deletion caused hypresensitivity, homologous recombination and DNA damage checkpoint genes were over-represented, suggesting that DNA double-strand breaks are a dominant cause of hydrogen selenide toxicity. Consistent with this hypothesis, treatment of S. cerevisiae cells with sodium selenide triggered G2/M checkpoint activation and induced in vivo chromosome fragmentation. In vitro, sodium selenide directly induced DNA phosphodiester-bond breaks via an O2-dependent reaction. The reaction was inhibited by mannitol, a hydroxyl radical quencher, but not by superoxide dismutase or catalase, strongly suggesting the involvement of hydroxyl radicals and ruling out participations of superoxide anions or hydrogen peroxide. The •OH signature could indeed be detected by electron spin resonance upon exposure of a solution of sodium selenide to O2. Finally we showed that, in vivo, toxicity strictly depended on the presence of O2. Therefore, by combining genome-wide and biochemical approaches, we demonstrated that, in yeast cells, hydrogen selenide induces toxic DNA breaks through an O2-dependent radical-based mechanism.

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Genotoxicity of selenite in diploid yeast

Cited by 24 publications

References 20 publications

Identification of genes affecting selenite toxicity and resistance in Saccharomyces cerevisiae

Identification of genes affecting selenite toxicity and resistance in Saccharomyces cerevisiae

Extracellular Production of Hydrogen Selenide Accounts for Thiol-assisted Toxicity of Selenite against Saccharomyces cerevisiae

Sodium Selenide Toxicity Is Mediated by O2-Dependent DNA Breaks

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