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

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

Item Type: Article
Uncontrolled Keywords: CDK, Histone H3K36 modification, MBF, Schizosaccharomyces pombe, Set2, Synthetic lethality, Wee1
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 07 Feb 2020 11:41
Last Modified: 07 Feb 2020 12:15
URI: http://repository.essex.ac.uk/id/eprint/26688

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