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
Authors | 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. |
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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 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. |
Journal | Journal of Cell Science |
Journal citation | 132 (6), p. jcs226969 |
ISSN | 0021-9533 |
Year | 2019 |
Publisher | The Company of Biologists Ltd |
Accepted author manuscript | License File Access Level Repository staff only |
Publisher's version | License |
Digital Object Identifier (DOI) | https://doi.org/10.1242/jcs.226969 |
Web address (URL) | https://doi.org/10.1242/jcs.226969 |
Publication dates | |
Online | 23 Jan 2019 |
25 Mar 2019 | |
Publication process dates | |
Deposited | 11 Feb 2019 |
Accepted | 02 Jan 2019 |
Accepted | 02 Jan 2019 |
Funder | Medical 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 |
https://repository.uel.ac.uk/item/8442w
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