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An essential role for dNTP homeostasis following CDK-induced replication stress
- Source :
- Journal of Cell Science
- Publication Year :
- 2018
- Publisher :
- Cold Spring Harbor Laboratory, 2018.
-
Abstract
- Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclin-dependent kinase (CDK)-induced replication stress, resulting from Wee1 inactivation, is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage and to genome instability. Cells respond to this replication stress by increasing dNTP supply through histone methyltransferase Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.<br />Highlighted Article: Replication stress is a source of genome instability. In this study in fission yeast, we describe a new role for the mitotic inhibitor Wee1 in suppressing replication stress and genome instability.
- Subjects :
- Set2
DNA Replication
Genome instability
Synthetic lethality
DNA damage
CDK
Cell Cycle Proteins
MBF
Origin of replication
Methylation
Histones
03 medical and health sciences
0302 clinical medicine
Cyclin-dependent kinase
Schizosaccharomyces
Wee1
Histone H3K36 modification
Homeostasis
heterocyclic compounds
030304 developmental biology
DNA integrity checkpoint
0303 health sciences
biology
Nucleotides
Chemistry
DNA replication
Cell Cycle Checkpoints
Histone-Lysine N-Methyltransferase
Protein-Tyrosine Kinases
Cyclin-Dependent Kinases
Cell biology
Histone Code
enzymes and coenzymes (carbohydrates)
Ribonucleotide reductase
Schizosaccharomyces pombe
030220 oncology & carcinogenesis
biology.protein
Schizosaccharomyces pombe Proteins
Synthetic Lethal Mutations
Research Article
DNA Damage
Transcription Factors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Journal of Cell Science
- Accession number :
- edsair.doi.dedup.....f0115607fec4978c6986b56635e11bc5
- Full Text :
- https://doi.org/10.1101/395715