The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1
Open accessAbstract
Cell cycle checkpoints are evolutionarily conserved surveillance systems that protect genomic stability and prevent oncogenesis in mammals. One important target of checkpoint control is ribonucleotide reductase (RNR), which catalyzes the rate-limiting step in dNTP and DNA synthesis. In both yeast and humans, RNR is transcriptionally induced after DNA damage via Mec1/Rad53 (yeast) and ATM/CHK2 (human) checkpoint pathways. In addition, yeast checkpoint proteins Mec1 and Rad53 also regulate the RNR inhibitor Sml1. After DNA damage or at S phase, Mec1 and Rad53 control the phosphorylation and concomitant degradation of Sml1 protein. This new layer of control contributes to the increased dNTP production likely necessary for DNA repair and replication; however, the molecular mechanism is unclear. Here we show that Dun1, a downstream kinase of Mec1/Rad53, genetically and physically interacts with Sml1 in vivo . The absence of Dun1 activity leads to the accumulation of Sml1 protein at S phase and after DNA damage. As a result, dun1 Δ strains need more time to finish DNA replication, are defective in mitochondrial DNA propagation, and are sensitive to DNA-damaging agents. Moreover, phospho-Sml1 is absent or dramatically reduced in dun1 Δ cells. Finally, Dun1 can phosphorylate Sml1 in vitro . These results suggest that Dun1 kinase function is the last step required in the Mec1/Rad53 cascade to remove Sml1 during S phase and after DNA damage.
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Checkpoints actively stimulate repair processes and, in higher eukaryotes, trigger apoptosis when damage cannot be successfully dealt with.
“The checkpoints also actively stimulate the repair processes [1–9] and, in higher eukaryotes, trigger the apoptotic response, if damage cannot be dealt with successfully [10–12].”
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- Authors
- Zhao, X., & Rothstein, R.
- Affiliations
- Columbia University (US)
- Cold Spring Harbor Laboratory (US)
- Corresponding author
- Rothstein, Rodney
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-03-19
- Volume
- 99
- Issue
- 6
- Pages
- 3746-3751
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC122595
- OpenAlex
- W2078957361
- Cited by
- 290
- References
- 24
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 15 · 2023: 3 · 2022: 12 · 2021: 11 · 2020: 6 · 2019: 10 · 2018: 7 · 2017: 9 · 2016: 10 · 2015: 14 · 2014: 18 · 2013: 16 · 2012: 17
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Baylor University
- Frances McClelland Institute for Children, Youth, and Families
- National Institutes of Health (GM50237)
- National Institute of General Medical Sciences (R01GM050237, GM 50237, R37GM050237)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- ribonucleotide reductase, cell cycle checkpoints, DNA damage response, protein phosphorylation, protein degradation, S phase, DNA replication, DNA-damaging agents, Saccharomyces cerevisiae
- MeSH terms
- Trefoil Factor-2, Alleles, Cell Division, DNA Damage, Enzyme Inhibitors, Fungal Proteins, Genes, Lethal, Models, Biological, Phenotype, Phosphorylation, Protein Binding, Protein Kinases, Ribonucleotide Reductases, Saccharomyces cerevisiae, S Phase, Protein Serine-Threonine Kinases, Gene Deletion, Cell Cycle Proteins, Two-Hybrid System Techniques, Saccharomyces cerevisiae Proteins, Intracellular Signaling Peptides and Proteins, Checkpoint Kinase 2
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