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An essential role for dNTP homeostasis following CDK-induced replication stress
journal contribution
posted on 2023-06-09, 17:26 authored by Chen-Chen Pai, Kuo-Feng Hsu, Samuel C Durley, Andrea KeszthelyiAndrea Keszthelyi, Stephen E Kearsey, Charalampos Rallis, Lisa K Folkes, Rachel Deegan, Sarah E Wilkins, Sophia X Pfister, Nagore De Leo´n, Christopher J Schofield, Ju¨rg Ba¨hler, Antony CarrAntony Carr, Timothy C HumphreyReplication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclindependent 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 trimethylation 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.
Funding
Replication fork stability and fork restart; G0745; MRC-MEDICAL RESEARCH COUNCIL; G1100074-E01/1
Single Molecule Imaging of the DNA Damage Response in Live Cells; G0250; EUROPEAN UNION; 268788
History
Publication status
- Published
File Version
- Published version
Journal
Journal of Cell ScienceISSN
0021-9533Publisher
Company of BiologistsExternal DOI
Issue
6Volume
132Page range
jcs226969 1-16Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-04-03First Open Access (FOA) Date
2019-04-03First Compliant Deposit (FCD) Date
2019-04-03Usage metrics
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