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Originally published In Press as doi:10.1074/jbc.M008871200 on February 6, 2001

J. Biol. Chem., Vol. 276, Issue 19, 16580-16586, May 11, 2001
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ATM-dependent Phosphorylation of Human Rad9 Is Required for Ionizing Radiation-induced Checkpoint Activation*

Ming-Jiu ChenDagger , Yi-Tzu LinDagger , Howard B. Lieberman§, Gang ChenDagger , and Eva Y.-H. P. LeeDagger ||

From the Dagger  Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center, San Antonio, Texas 78245-3207 and the § Center for Radiological Research, Columbia University, New York, New York 10032

ATM (ataxia-telangiectasia-mutated) is a Ser/Thr kinase involved in cell cycle checkpoints and DNA repair. Human Rad9 (hRad9) is the homologue of Schizosaccharomyces pombe Rad9 protein that plays a critical role in cell cycle checkpoint control. To examine the potential signaling pathway linking ATM and hRad9, we investigated the modification of hRad9 in response to DNA damage. Here we show that hRad9 protein is constitutively phosphorylated in undamaged cells and undergoes hyperphosphorylation upon treatment with ionizing radiation (IR), ultraviolet light (UV), and hydroxyurea (HU). Interestingly, hyperphosphorylation of hRad9 induced by IR is dependent on ATM. Ser272 of hRad9 is phosphorylated directly by ATM in vitro. Furthermore, hRad9 is phosphorylated on Ser272 in response to IR in vivo, and this modification is delayed in ATM-deficient cells. Expression of hRad9 S272A mutant protein in human lung fibroblast VA13 cells disturbs IR-induced G1/S checkpoint activation and increased cellular sensitivity to IR. Together, our results suggest that the ATM-mediated phosphorylation of hRad9 is required for IR-induced checkpoint activation.

* This work was supported by National Institutes of Health Grants CA81020 and NS37381 (to E. L.) and GM52493 (to H. B. L.).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.

Current address: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd., Tarrytown, NY 10591-6707.

|| To whom correspondence should be addressed. Tel.: 210-567-7326; Fax: 210-567-7324; E-mail: leee@uthscsa.edu.

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