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

Article

Pai, Chen-Chun, Hsu, Kuo-Feng, Durley, Samuel C., Keszthelyi, Andrea, Kearsey, Stephen E., Rallis, C., Folkes, Lisa K., Deegan, Rachel, Wilkins, Sarah E., Pfister, Sophia X., De Leόn, Nagore, Schofield, Christopher J., Bähler, Jürg, 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), p. jcs226969. https://doi.org/10.1242/jcs.226969
AuthorsPai, Chen-Chun, Hsu, Kuo-Feng, Durley, Samuel C., Keszthelyi, Andrea, Kearsey, Stephen E., Rallis, C., Folkes, Lisa K., Deegan, Rachel, Wilkins, Sarah E., Pfister, Sophia X., De Leόn, Nagore, Schofield, Christopher J., Bähler, Jürg, Carr, Antony M. and Humphrey, Timothy C.
Abstract

Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here we show that CDK-induced replication stress 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 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.

JournalJournal of Cell Science
Journal citation132 (6), p. jcs226969
ISSN0021-9533
Year2019
PublisherThe Company of Biologists Ltd
Accepted author manuscript
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Digital Object Identifier (DOI)https://doi.org/10.1242/jcs.226969
Web address (URL)https://doi.org/10.1242/jcs.226969
Publication dates
Online23 Jan 2019
Print25 Mar 2019
Publication process dates
Deposited11 Feb 2019
Accepted02 Jan 2019
Accepted02 Jan 2019
FunderMedical Research Council
Clarendon Scholarship
Cancer Research UK
European Research Council
Wellcome Trust
Biotechnology and Biological Sciences Research Council
Ministry of National Defense-Medical Affairs Bureau
Medical Research Council
Clarendon Scholarship
Cancer Research UK
European Research Council
Medical Research Council
Wellcome Trust
Biotechnology and Biological Sciences Research Council
Medical Research Council
Ministry of National Defense-Medical Affairs Bureau
Copyright information© 2019 The authors
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