An essential role for dNTP homeostasis following CDKinduced [Pu-seq]

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 MBFinduced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through loss of Set2-dependent H3K36 tri-methylation, results in further dNTP depletion due to reduced RNR expression, leading to replication catastrophe and cell death. This lethality can be rescued by increasing dNTP levels. Similarly, we find loss of the DNA integrity checkpoint results in synthetic lethality with Wee1 inactivation, which is also associated with replication collapse through critically low dNTP levels. Together, these findings support a ‘dNTP supply and demand’ model in which maintaining dNTP homeostasis is essential in preventing replication catastrophe in response to CDK-induced replication stress.

ORGANISM(S): Schizosaccharomyces pombe

PROVIDER: GSE113747 | GEO | 2018/05/26

REPOSITORIES: GEO