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Oxidative protein damage causes chromium toxicity in yeast

¹ School of Biology, Institute of Genetics, University of Nottingham, University Park, Nottingham NG7 2RD, UK
² Department of Biology, Georgia State University, University Plaza, Atlanta, GA 30303, USA

Correspondence
Simon V. Avery
Simon.Avery{at}nottingham.ac.uk

Oxidative damage in microbial cells occurs during exposure to the toxic metal chromium, but it is not certain whether such oxidation accounts for the toxicity of Cr. Here, a Saccharomyces cerevisiae sod1 mutant (defective for the Cu,Zn-superoxide dismutase) was found to be hypersensitive to Cr(VI) toxicity under aerobic conditions, but this phenotype was suppressed under anaerobic conditions. Studies with cells expressing a Sod1p variant (Sod1^H46C) showed that the superoxide dismutase activity rather than the metal-binding function of Sod1p was required for Cr resistance. To help identify the macromolecular target(s) of Cr-dependent oxidative damage, cells deficient for the reduction of phospholipid hydroperoxides (gpx3 and gpx1/gpx2/gpx3) and for the repair of DNA oxidation (ogg1 and rad30/ogg1) were tested, but were found not to be Cr-sensitive. In contrast, S. cerevisiae msra (mxr1) and msrb (ycl033c) mutants defective for peptide methionine sulfoxide reductase (MSR) activity exhibited a Cr sensitivity phenotype, and cells overexpressing these enzymes were Cr-resistant. Overexpression of MSRs also suppressed the Cr sensitivity of sod1 cells. The inference that protein oxidation is a primary mechanism of Cr toxicity was corroborated by an observed 20-fold increase in the cellular levels of protein carbonyls within 30 min of Cr exposure. Carbonylation was not distributed evenly among the expressed proteins of the cells; certain glycolytic enzymes and heat-shock proteins were specifically targeted by Cr-dependent oxidative damage. This study establishes an oxidative mode of Cr toxicity in S. cerevisiae, which primarily involves oxidative damage to cellular proteins.

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