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

SUBMITTER: Moiseeva TN 

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

REPOSITORIES: biostudies-literature