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


Nerea Sanvisens

Antonia M. Romero

Xiuxiang An

Caiguo Zhang

Rosa de Llanos


M. Carmen

Mingxia Huang

Sergi Puig


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 dun1? and fet3? fet4? mutants, which is rescued by SML1 deletion. Consistent with an increase in RNR function, Rnr1 protein levels are upregulated upon Fe deficiency. Finally, dun1? 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.


Sanvisens, N., Romero, A. M., An, X., Zhang, C., de Llanos, R., Martinez-Pastor, M. T., …Puig, S. (2014). Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Inhibitor Sml1 in Response to Iron Deficiency. Molecular and Cellular Biology, 34(17), 3259-3271.

Journal Article Type Article
Acceptance Date Jun 12, 2014
Online Publication Date Jun 23, 2014
Publication Date Sep 1, 2014
Deposit Date Sep 22, 2016
Journal Molecular and Cellular Biology
Print ISSN 0270-7306
Electronic ISSN 1098-5549
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 34
Issue 17
Pages 3259-3271
Keywords eukaryotic organisms, micronutrient, redox-active cofactor, DNA replication,
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