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ATR, Claspin and the Rad9-Rad1-Hus1 Complex Regulate Chk1 and Cdc25A in the Absence of DNA Damage
Claus Storgaard Sørensen, Randi G. Syljuåsen, Jiri Lukas and Jiri Bartek
volume 3 | issue 7
july 2004Pages: 941 - 945
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The ATR and Chk1 kinases are essential to maintain genomic integrity. ATR, with Claspin and the Rad9-Rad1-Hus1 complex, activates Chk1 after DNA damage. Chk1-mediated phosphorylation of the Cdc25A phosphatase is required for the mammalian S-phase checkpoint. Here, we show that during physiological S phase the regulation of the Chk1-Cdc25A pathway depends on ATR, Claspin, Rad9, and Hus1. Human cells with chemically or genetically ablated ATR showed inhibition of Chk1-dependent phosphorylation of Cdc25A, and they accumulated Cdc25A without external DNA damage. Furthermore, siRNA-mediated depletion of Claspin, Rad9 and Hus1 also stabilized Cdc25A. ATR ablation also inhibited the activatory phosphorylation of Chk1 on serine 345. Thus, the ATR-Chk1-Cdc25A pathway represents an integral part of physiological S-phase progression, and interference with this mechanism undermines viability of somatic mammalian cells. DNA damage further activates and switches this pathway from its constitutively operating “surveillance mode” compatible with DNA replication into an “emergency” checkpoint response.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDF If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.