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Iron regulation through the back door: iron-dependent metabolite levels contribute to transcriptional adaptation to iron deprivation in Saccharomyces cerevisiae.

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.

Pubmed ID: 20008079


  • Ihrig J
  • Hausmann A
  • Hain A
  • Richter N
  • Hamza I
  • Lill R
  • Mühlenhoff U


Eukaryotic cell

Publication Data

March 3, 2010

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK074797
  • Agency: NIDDK NIH HHS, Id: R01 DK074797-01

Mesh Terms

  • 3-Isopropylmalate Dehydrogenase
  • CCAAT-Binding Factor
  • Ceruloplasmin
  • Cytochromes c
  • DNA-Binding Proteins
  • Down-Regulation
  • Ferrochelatase
  • Gene Expression
  • Gene Expression Regulation, Fungal
  • Heme
  • Homeostasis
  • Hydro-Lyases
  • Iron
  • Iron Chelating Agents
  • Isomerases
  • Malates
  • Peroxidases
  • Phenanthrolines
  • Promoter Regions, Genetic
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Terminator Regions, Genetic
  • Trans-Activators
  • Transcription Factors
  • Tristetraprolin
  • Up-Regulation