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Publication Detail
An essential role for dNTP homeostasis following CDK-induced replication stress
  • Publication Type:
    Working discussion paper
  • Authors:
    Pai C-C, Hsu K-F, Durley S, Keszthelyi A, Kearsey S, Rallis C, Folkes L, Deegan R, Wilkins S, Pfister S, León ND, Schofield C, Bähler J, Carr A, Humphrey T
  • Publication date:
    03/09/2018
  • Status:
    Published
Abstract
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, Mus81-dependent 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.
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