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Originally published as MBC in Press, 10.1091/mbc.E07-11-1173 on April 16, 2008

Vol. 19, Issue 7, 2995-3007, July 2008

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Gcn4 Is Required for the Response to Peroxide Stress in the Yeast Saccharomyces cerevisiae

Claire Mascarenhas, Laura C. Edwards-Ingram, Leo Zeef, Daniel Shenton, Mark P. Ashe, and Chris M. Grant

The University of Manchester, Faculty of Life Sciences, Manchester M13 9PT, United Kingdom

Submitted November 26, 2007; Revised March 31, 2008; Accepted April 9, 2008
Monitoring Editor: Thomas Fox

An oxidative stress occurs when reactive oxygen species overwhelm the cellular antioxidant defenses. We have examined the regulation of protein synthesis in Saccharomyces cerevisiae in response to oxidative stress induced by exposure to hydroperoxides (hydrogen peroxide, and cumene hydroperoxide), a thiol oxidant (diamide), and a heavy metal (cadmium). Examination of translational activity indicates that these oxidants inhibit translation at the initiation and postinitiation phases. Inhibition of translation initiation in response to hydroperoxides is entirely dependent on phosphorylation of the {alpha} subunit of eukaryotic initiation factor (eIF)2 by the Gcn2 kinase. Activation of Gcn2 is mediated by uncharged tRNA because mutation of its HisRS domain abolishes regulation in response to hydroperoxides. Furthermore, Gcn4 is translationally up-regulated in response to H2O2, and it is required for hydroperoxide resistance. We used transcriptional profiling to identify a wide range of genes that mediate this response as part of the Gcn4-dependent H2O2-regulon. In contrast to hydroperoxides, regulation of translation initiation in response to cadmium and diamide depends on both Gcn2 and the eIF4E binding protein Eap1. Thus, the response to oxidative stress is mediated by oxidant-specific regulation of translation initiation, and we suggest that this is an important mechanism underlying the ability of cells to adapt to different oxidants.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E07-11-1173) on April 16, 2008.

Address correspondence to: Chris M. Grant (chris.grant{at}manchester.ac.uk)






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