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J. Biol. Chem., Vol. 281, Issue 14, 9346-9350, April 7, 2006

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Rapid Activation of ATR by Ionizing Radiation Requires ATM and Mre11^*

From the Department of Biochemistry, Vanderbilt University, Nashville, Tennessee 37232

The ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases are crucial regulatory proteins in genotoxic stress response pathways that pause the cell cycle to permit DNA repair. Here we show that Chk1 phosphorylation in response to hydroxyurea and ultraviolet radiation is ATR-dependent and ATM- and Mre11-independent. In contrast, Chk1 phosphorylation in response to ionizing radiation (IR) is dependent on ATR, ATM, and Mre11. The ATR and ATM/Mre11 pathways are generally thought to be separate with ATM activation occurring early and ATR activation occurring as a late response to double strand breaks. However, we demonstrate that ATR is activated rapidly by IR, and ATM and Mre11 enhance ATR signaling. ATR-ATR-interacting protein recruitment to double strand breaks is less efficient in the absence of ATM and Mre11. Furthermore, IR-induced replication protein A foci formation is defective in ATM- and Mre11-deficient cells. Thus, ATM and Mre11 may stimulate the ATR signaling pathway by converting DNA damage generated by IR into structures that recruit and activate ATR.

Received for publication, December 13, 2005 , and in revised form, January 23, 2006.

^* This work was supported in part by NCI, National Institutes of Health Grant RO1CA102729 (to D. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-3.

¹ Supported by National Institutes of Health Training Grants T32CA093240 and T32CA009582.

² To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt University, Nashville, TN 37232. Tel.: 615-322-8547; Fax: 615-343-0704; E-mail: david.cortez{at}vanderbilt.edu.

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