Abstract
Budding yeast (Saccharomyces cerevisiae) responds to iron deprivation both by Aft1-Aft2-dependent transcriptional activation of genes involved in cellular iron uptake and by Cth1-Cth2-specific degradation of certain mRNAs coding for iron-dependent biosynthetic components. Here, we provide evidence for a novel principle of iron-responsive gene expression. This regulatory mechanism is based on the modulation of transcription through the iron-dependent variation of levels of regulatory metabolites. As an example, the LEU1 gene of branched-chain amino acid biosynthesis is downregulated under iron-limiting conditions through depletion of the metabolic intermediate alpha-isopropylmalate, which functions as a key transcriptional coactivator of the Leu3 transcription factor. Synthesis of alpha-isopropylmalate involves the iron-sulfur protein Ilv3, which is inactivated under iron deficiency. As another example, decreased mRNA levels of the cytochrome c-encoding CYC1 gene under iron-limiting conditions involve heme-dependent transcriptional regulation via the Hap1 transcription factor. Synthesis of the iron-containing heme is directly correlated with iron availability. Thus, the iron-responsive expression of genes that are downregulated under iron-limiting conditions is conferred by two independent regulatory mechanisms: transcriptional regulation through iron-responsive metabolites and posttranscriptional mRNA degradation. Only the combination of the two processes provides a quantitative description of the response to iron deprivation in yeast.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Isopropylmalate Dehydrogenase / genetics
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CCAAT-Binding Factor / genetics
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Ceruloplasmin / genetics
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Cytochromes c / genetics
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Cytochromes c / metabolism
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DNA-Binding Proteins / genetics
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Down-Regulation / genetics
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Ferrochelatase / metabolism
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Gene Expression / drug effects
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Gene Expression / genetics
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Gene Expression Regulation, Fungal / physiology*
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Heme / metabolism*
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Homeostasis / physiology*
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Hydro-Lyases / genetics
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Hydro-Lyases / metabolism
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Iron / metabolism*
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Iron Chelating Agents / pharmacology
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Iron Deficiencies
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Isomerases / genetics
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Isomerases / metabolism
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Malates / metabolism*
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Malates / pharmacology
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Peroxidases / genetics
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Phenanthrolines / pharmacology
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Promoter Regions, Genetic / genetics
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism*
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Terminator Regions, Genetic / genetics
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Trans-Activators / genetics
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Transcription Factors / genetics
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Tristetraprolin / genetics
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Up-Regulation / genetics
Substances
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AFT1 protein, S cerevisiae
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CCAAT-Binding Factor
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CTH1 protein, S cerevisiae
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CYC1 protein, S cerevisiae
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DNA-Binding Proteins
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HAP1 protein, S cerevisiae
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HAP4 protein, S cerevisiae
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Iron Chelating Agents
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LEU3 protein, S cerevisiae
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Malates
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Phenanthrolines
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Saccharomyces cerevisiae Proteins
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TIS11 protein, S cerevisiae
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Trans-Activators
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Transcription Factors
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Tristetraprolin
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alpha-isopropylmalate
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Heme
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bathophenanthroline
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Cytochromes c
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Iron
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3-Isopropylmalate Dehydrogenase
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LEU2 protein, S cerevisiae
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HMX1 protein, S cerevisiae
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Peroxidases
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Ceruloplasmin
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FET3 protein, S cerevisiae
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Hydro-Lyases
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isopropylmalate isomerase
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dihydroxyacid dehydratase
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Ferrochelatase
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Isomerases