Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Inhibitor Sml1 in Response to Iron Deficiency

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RESEARCH PRODUCT

Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Inhibitor Sml1 in Response to Iron Deficiency

María Teresa Martínez-pastor Caiguo Zhang Antonia María Romero Sergi Puig M. Carmen Bañó Nerea Sanvisens Rosa De Llanos Mingxia Huang Xiuxiang An

subject

Iron-Sulfur Proteins Proteasome Endopeptidase Complex Saccharomyces cerevisiae Proteins Deoxyribonucleoside triphosphate Ribonucleotide Iron Deoxyribonucleotides Genes Fungal Saccharomyces cerevisiae Cell Cycle Proteins Saccharomyces cerevisiae Ribonucleotide reductase inhibitor Protein Serine-Threonine Kinases Biology Protein degradation chemistry.chemical_compound Tristetraprolin Ribonucleotide Reductases Aspartic Acid Endopeptidases Phosphorylation Molecular Biology Checkpoint Kinase 2 Binding Sites Kinase Intracellular Signaling Peptides and Proteins Articles Cell Biology biology.organism_classification DNA-Binding Proteins Deoxyribonucleoside Checkpoint Kinase 2 chemistry Biochemistry Proteolysis Gene Deletion Transcription Factors

description

Iron is an essential micronutrient for all eukaryotic organisms because it participates as a redox-active cofactor in many biological processes, including DNA replication and repair. Eukaryotic ribonucleotide reductases (RNRs) are Fe-dependent enzymes that catalyze deoxyribonucleoside diphosphate (dNDP) synthesis. We show here that the levels of the Sml1 protein, a yeast RNR large-subunit inhibitor, specifically decrease in response to both nutritional and genetic Fe deficiencies in a Dun1-dependent but Mec1/Rad53- and Aft1-independent manner. The decline of Sml1 protein levels upon Fe starvation depends on Dun1 forkhead-associated and kinase domains, the 26S proteasome, and the vacuolar proteolytic pathway. Depletion of core components of the mitochondrial iron-sulfur cluster assembly leads to a Dun1-dependent diminution of Sml1 protein levels. The physiological relevance of Sml1 downregulation by Dun1 under low-Fe conditions is highlighted by the synthetic growth defect observed between dun1Δ and fet3Δ fet4Δ mutants, which is rescued by SML1 deletion. Consistent with an increase in RNR function, Rnr1 protein levels are upregulated upon Fe deficiency. Finally, dun1Δ mutants display defects in deoxyribonucleoside triphosphate (dNTP) biosynthesis under low-Fe conditions. Taken together, these results reveal that the Dun1 checkpoint kinase promotes RNR function in response to Fe starvation by stimulating Sml1 protein degradation.

year	journal	country	edition	language
2014-09-01	Molecular and Cellular Biology

https://doi.org/10.1128/mcb.00472-14