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A more recent version of this article appeared on April 1, 2006
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Submitted on September 18, 2005
Revised on December 20, 2005
Accepted on January 13, 2006
Department of Molecular Pharmacology, Stanford University, Stanford, CA 94305-5441
Monitoring Editor: John York
The DNA damage checkpoint pathways sense and respond to DNA damage in order to ensure genomic stability. The ATR kinase is a central regulator of one such pathway and phosphorylates a number of proteins that have roles in cell cycle progression and DNA repair. Using the Xenopus egg extract system, we have investigated regulation of the RHR (Rad1/Hus1/Rad9) complex. We show here that phosphorylation of Rad1 and Hus1 occurs in an ATR- and TopBP1-dependent manner on T5 of Rad1 and S219 and T223 of Hus1. Mutation of these sites has no effect on the phosphorylation of Chk1 by ATR. Interestingly, phosphorylation of Rad1 is independent of Claspin and the Rad9 carboxy-terminus, both of which are required for Chk1 phosphorylation. These data suggest that an active ATR signaling complex exists in the absence of the carboxy-terminus of Rad9, and that this carboxy-terminal domain may be a specific requirement for Chk1 phosphorylation and not necessary for all ATR-mediated signaling events. Thus, Rad1 phosphorylation provides an alternate and early readout for the study of ATR activation.
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