title: Gcn4 is required for the response to peroxide stress in the yeast Saccharomyces cerevisiae.
abstract: 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 H(2)O(2), 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 H(2)O(2)-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.
authors.affiliation: The University of Manchester, Faculty of Life Sciences, Manchester M13 9PT, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Mascarenhas
authors.forename: Laura C
authors.initials: LC
authors.lastname: Edwards-Ingram
authors.forename: Leo
authors.initials: L
authors.lastname: Zeef
authors.forename: Daniel
authors.initials: D
authors.lastname: Shenton
authors.forename: Mark P
authors.initials: MP
authors.lastname: Ashe
authors.forename: Chris M
authors.initials: CM
authors.lastname: Grant
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D016877:Oxidants / Q000737:chemistry; D018384:Oxidative Stress; D010448:Peptide Initiation Factors / Q000378:metabolism; D010545:Peroxides / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C501391:GCN4 protein, S cerevisiae; D016877:Oxidants; D010448:Peptide Initiation Factors; D010545:Peroxides; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C410795:eIF4E-associated protein Eap1; D006861:Hydrogen Peroxide; C512912:GCN2 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases