title: Yeast Dun1 kinase regulates ribonucleotide reductase inhibitor Sml1 in response to iron deficiency.
abstract: 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.
authors: Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), Paterna, Valencia, Spain.
authors: Nerea
authors: N
authors: Sanvisens
authors: Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), Paterna, Valencia, Spain.
authors: Antonia M
authors: AM
authors: Romero
authors: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Denver, Colorado, USA.
authors: Xiuxiang
authors: X
authors: An
authors: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Denver, Colorado, USA.
authors: Caiguo
authors: C
authors: Zhang
authors: Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), Paterna, Valencia, Spain.
authors: Rosa
authors: R
authors: de Llanos
authors: Departamento de Bioquímica y Biología Molecular, Universitat de València, Burjassot, Valencia, Spain.
authors: María Teresa
authors: MT
authors: Martínez-Pastor
authors: Departamento de Bioquímica y Biología Molecular, Universitat de València, Burjassot, Valencia, Spain.
authors: M Carmen
authors: MC
authors: Bañó
authors: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Denver, Colorado, USA mingxia.huang@ucdenver.edu spuig@iata.csic.es.
authors: Mingxia
authors: M
authors: Huang
authors: Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), Paterna, Valencia, Spain mingxia.huang@ucdenver.edu spuig@iata.csic.es.
authors: Sergi
authors: S
authors: Puig
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000096:biosynthesis; D017353:Gene Deletion; D005800:Genes, Fungal; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051816:Tristetraprolin / Q000235:genetics / Q000378:metabolism
chemical_list: C090297:AFT1 protein, S cerevisiae; C102098:CTH1 protein, S cerevisiae; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D003854:Deoxyribonucleotides; D047908:Intracellular Signaling Peptides and Proteins; D007506:Iron-Sulfur Proteins; C115052:SML1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C091790:TIS11 protein, S cerevisiae; D014157:Transcription Factors; D051816:Tristetraprolin; D007501:Iron; D012264:Ribonucleotide Reductases; C551024:Rnr1 protein, S cerevisiae; C104169:DUN1 protein, S cerevisiae; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae; C499267:PEP4 protein, S cerevisiae; D016282:Aspartic Acid Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease