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Originally published In Press as doi:10.1074/jbc.M105152200 on September 10, 2001

J. Biol. Chem., Vol. 276, Issue 45, 41898-41905, November 9, 2001
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DNA Damage-dependent and -independent Phosphorylation of the hRad9 Checkpoint Protein*

Robert P. St.OngeDagger §, Blair D. A. BesleyDagger ||**, Minwoo ParkDagger ||, Richard CasselmanDagger , and Scott DaveyDagger §||Dagger Dagger §§

From the Dagger  Cancer Research Laboratories and the Departments of § Pathology, || Biochemistry, and Dagger Dagger  Oncology, Queen's University, Kingston, Ontario K7L 3N6, Canada

Cell cycle checkpoints are regulatory mechanisms that maintain genomic integrity by preventing cell cycle progression when genetic anomalies are present. The hRad9 protein is the human homologue of Schizosaccharomyces pombe Rad9, a checkpoint protein required for preventing the onset of mitosis if DNA damage is present or if DNA replication is incomplete. Genetic and biochemical analyses indicate that hRad9 is a component of the checkpoint response in humans and has possible roles in regulating the cell cycle, apoptosis, and DNA repair. Previous studies indicate that hRad9 is modified by phosphorylation, both in the absence of exogenous stress and in response to various genotoxins. In this study, we report the mapping of several sites of constitutive phosphorylation of hRad9 to (S/T)PX(R/P) sequences near the C terminus of the protein. We also demonstrate that a serine to alanine mutation at residue 272 abrogates an ionizing radiation (IR)-induced phosphorylation of hRad9 and further show that phosphorylation at (S/T)P sites is not a prerequisite for IR-induced phosphorylation of serine 272. Finally, we report that hRad9 undergoes cell cycle-regulated hyper-phosphorylation in G2/M that is enhanced by IR but distinct from that on serine 272. Unlike the IR-induced phosphorylation at serine 272, this event is dependent on serine 277 and threonine 292, two C-terminal (S/T)P sites in hRad9.

* This work was supported by Canadian Institutes of Health Research Grants MOP-14352 and MOP-36526 and National Institutes of Health Grant E507940 (to S. D.). Flow cytometry was funded in part by Canadian Institutes of Health Research Grant MT-7827.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a National Cancer Institute of Canada studentship.

** Recipient of U. S. Army Breast Cancer Research Studentship DAMD17-98-1-8080.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§§ A Cancer Care Ontario Scientist. To whom correspondence should be addressed: Cancer Research Laboratories, Queen's University, Kingston, Ontario, K7L 3N6, Canada. Tel.: 613-533-6923; Fax: 613-533-6830; E-mail: sd13@post.queensu.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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