An essential role for dNTP homeostasis following CDK-induced replication stress

Pai, Chen-Chen, Hsu, Kuo-Feng, Durley, Samuel C, Keszthelyi, Andrea, Kearsey, Stephen E, Rallis, Charalampos, Folkes, Lisa K, Deegan, Rachel, Wilkins, Sarah E, Pfister, Sophia X, De León, Nagore, Schofield, Christopher J, Bähler, Jürg, Carr, Antony and Humphrey, Timothy C (2019) An essential role for dNTP homeostasis following CDK-induced replication stress. Journal of Cell Science, 132 (6). jcs226969 1-16. ISSN 0021-9533

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Abstract

Replication 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Subjects: Q Science
Depositing User: Paula Amiet-West
Date Deposited: 03 Apr 2019 09:15
Last Modified: 03 Apr 2019 09:15
URI: http://srodev.sussex.ac.uk/id/eprint/82948

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Project NameSussex Project NumberFunderFunder Ref
Single Molecule Imaging of the DNA Damage Response in Live CellsG0250EUROPEAN UNION268788
Replication fork stability and fork restartG0745MRC-MEDICAL RESEARCH COUNCILG1100074-E01/1