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J. Biol. Chem., Vol. 282, Issue 4, 2184-2195, January 26, 2007

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Regulation of the Yeast TSA1 Peroxiredoxin by ZAP1 Is an Adaptive Response to the Oxidative Stress of Zinc Deficiency^*

Chang-Yi Wu, Amanda J. Bird, Dennis R. Winge, and David J. Eide¹

From the Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706 and the Department of Biochemistry, University of Utah, Salt Lake City, Utah 84132

Zinc deficiency is a potential risk factor for disease in humans because it leads to increased oxidative stress and DNA damage. We show here that the yeast Saccharomyces cerevisiae also experiences oxidative stress when zinc-deficient, and we have identified one mechanism yeast cells use to defend themselves against this stress. The Zap1p transcription factor is a central player in the response of yeast to zinc deficiency. To identify genes important for growth in low zinc, DNA microarrays were used to identify genes directly regulated by Zap1p. We found that the TSA1 gene is one such Zap1p target whose expression is increased under zinc deficiency. TSA1 encodes a cytosolic thioredoxin-dependent peroxidase responsible for degrading hydrogen peroxide and organic hydroperoxides. Consistent with its regulation by Zap1p, we showed that tsa1 mutants have a growth defect in low zinc that can be suppressed by zinc but not by other metals. Anaerobic conditions also suppressed the tsa1 low zinc growth defect indicating that oxidative stress is the likely cause of the poor growth. Consistent with this hypothesis, we demonstrated that zinc deficiency causes increased reactive oxygen species in wild type cells and that this increase is further exacerbated in tsa1 mutants. The role of this regulation by Zap1p in limiting oxidative stress in low zinc was confirmed when the Zap1p-binding site was specifically mutated in the chromosomal TSA1 promoter. Thus, we conclude that TSA1 induction by Zap1p is an adaptive response to deal with the increased oxidative stress caused by zinc deficiency.

Received for publication, July 12, 2006 , and in revised form, October 30, 2006.

^* This work was supported by National Institutes of Health Grant GM56285. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Nutritional Sciences, 1415 Linden Dr., University of Wisconsin-Madison, Madison, WI 53706-1571; Tel.: 608-263-1613; Fax: 608-262-5860; E-mail: eide{at}nutrisci.wisc.edu.

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