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. 2010 Sep;24(6):1764-7.
doi: 10.1016/j.tiv.2010.07.006. Epub 2010 Jul 14.

Chromate-induced sulfur starvation and mRNA mistranslation in yeast are linked in a common mechanism of Cr toxicity

Sara L Holland  1 , Ekalabya Ghosh, Simon V Avery
Affiliations

Chromate-induced sulfur starvation and mRNA mistranslation in yeast are linked in a common mechanism of Cr toxicity

Sara L Holland et al. Toxicol In Vitro. 2010 Sep.

Abstract

Toxicity of the environmental carcinogen chromate is known to involve sulfur starvation and also error-prone mRNA translation. Here we reconcile those facts using the yeast model. We demonstrate that: (i) cysteine and methionine starvation mimic Cr-induced translation errors, (ii) genetic suppression of S starvation suppresses Cr-induced mistranslation, and (iii) mistranslation requires cysteine and methionine biosynthesis. Therefore, Cr-induced S starvation is the cause of mRNA mistranslation. This establishes a single, novel pathway mediating the toxicity of chromate.

Keywords: Chromate toxicity; Saccharomyces cerevisiae; Sul1; frameshift; sulfate transport.

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Figures

Fig. 1
Fig. 1
Met or Cys starvation mimics Cr-induced mRNA mistranslation. (A) S.cerevisiae BY4743 transformed with plasmid pYDL-TY1, which carries a dual-luciferase frameshift reporter construct, was cultured in YNB broth with appropriate supplements before treatment for 3 h with the indicated CrO3 concentrations and subsequent determination of luciferase activities. RLU, relative light units. All values are means ± SEM from at least three independent determinations. (B) Luciferase activities were from Met+/Cys+ prototrophs transformed with pYDL-TY1 and cultured overnight in YNB supplemented with Met and Cys as indicated. (C) Luciferase activities were from wild type Met+/Cys+ prototrophs and cys3Δ/met15Δ auxotrophic cells transformed with pYDL-TY1 and cultured overnight in YNB supplemented with 22μM Met and 83μM Cys. (D) A wild type Met+/Cys+ prototroph and a cys3Δ/met15Δ auxotrophic strain, both expressing the ade2-101 allele, were spotted in 10-fold serial dilutions on to YNB agar supplemented with Met and Cys as indicated. Images were captured after 4 d incubation at 30°C.
Fig. 2
Fig. 2
Chromate induced mistranslation requires the Sul1p/Sul2p transporters. Wild type cells (MATα his3Δ1 leu2Δ0 ura3Δ0) and a sul1Δ/sul2Δ double mutant were transformed with pYDL-TY1 and cultured in YNB broth, before treatment either without (open bars) or with (filled bars) 0.1 mM CrO3 for 3 h. Total protein was subsequently extracted for luciferase analysis. All values are means ± SEM from at least three independent determinations. Inset, cellular Cr levels were determined at the indicated intervals during Cr treatment of wild type and sul1Δ/sul2Δ cells, cultured as above.
Fig. 3
Fig. 3
Chromate induced mistranslation requires Cys/Met biosynthesis. Wild type cells (MATα his3Δ1 leu2Δ0 ura3Δ0) and a cys3Δ/met15Δ auxotrophic mutant, both transformed with pYDL-TY1, were cultured for 16 h in YNB supplemented with Met and Cys as indicated and in the absence (open bars) or presence (filled bars) of 0.1 mM CrO3. Total protein was subsequently extracted for luciferase analysis.
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