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An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication.


ABSTRACT: DNA damage-induced signaling by ATR and CHK1 inhibits DNA replication, stabilizes stalled and collapsed replication forks, and mediates the repair of multiple classes of DNA lesions. We and others have shown that ATR kinase inhibitors, three of which are currently undergoing clinical trials, induce excessive origin firing during unperturbed DNA replication, indicating that ATR kinase activity limits replication initiation in the absence of damage. However, the origins impacted and the underlying mechanism(s) have not been described. Here, we show that unperturbed DNA replication is associated with a low level of ATR and CHK1 kinase signaling and that inhibition of this signaling induces dormant origin firing at sites of ongoing replication throughout the S phase. We show that ATR and CHK1 kinase inhibitors induce RIF1 Ser2205 phosphorylation in a CDK1-dependent manner, which disrupts an interaction between RIF1 and PP1 phosphatase. Thus, ATR and CHK1 signaling suppresses CDK1 kinase activity throughout the S phase and stabilizes an interaction between RIF1 and PP1 in replicating cells. PP1 dephosphorylates key CDC7 and CDK2 kinase substrates to inhibit the assembly and activation of the replicative helicase. This mechanism limits origin firing during unperturbed DNA replication in human cells.

SUBMITTER: Moiseeva TN 

PROVIDER: S-EPMC6613105 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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An ATR and CHK1 kinase signaling mechanism that limits origin firing during unperturbed DNA replication.

Moiseeva Tatiana N TN   Yin Yandong Y   Calderon Michael J MJ   Qian Chenao C   Schamus-Haynes Sandra S   Sugitani Norie N   Osmanbeyoglu Hatice U HU   Rothenberg Eli E   Watkins Simon C SC   Bakkenist Christopher J CJ  

Proceedings of the National Academy of Sciences of the United States of America 20190617 27


DNA damage-induced signaling by ATR and CHK1 inhibits DNA replication, stabilizes stalled and collapsed replication forks, and mediates the repair of multiple classes of DNA lesions. We and others have shown that ATR kinase inhibitors, three of which are currently undergoing clinical trials, induce excessive origin firing during unperturbed DNA replication, indicating that ATR kinase activity limits replication initiation in the absence of damage. However, the origins impacted and the underlying  ...[more]

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