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Science 304 (5667): 93-96

Copyright © 2004 by the American Association for the Advancement of Science

Direct Activation of the ATM Protein Kinase by the Mre11/Rad50/Nbs1 Complex

Ji-Hoon Lee, and Tanya T. Paull*

Abstract: The complex containing the Mre11, Rad50, and Nbs1 proteins (MRN) is essential for the cellular response to DNA double-strand breaks, integrating DNA repair with the activation of checkpoint signaling through the protein kinase ATM (ataxia telangiectasia mutated). We demonstrate that MRN stimulates the kinase activity of ATM in vitro toward its substrates p53, Chk2, and histone H2AX. MRN makes multiple contacts with ATM and appears to stimulate ATM activity by facilitating the stable binding of substrates. Phosphorylation of Nbs1 is critical for MRN stimulation of ATM activity toward Chk2, but not p53. Kinase-deficient ATM inhibits wild-type ATM phosphorylation of Chk2, consistent with the dominant-negative effect of kinase-deficient ATM in vivo.

Department of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, 1 University Station, A4800, Austin, TX 78712, USA.

* To whom correspondence should be addressed. E-mail: tpaull{at}

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Targeting of p300/CREB Binding Protein Coactivators by Simian Virus 40 Is Mediated through p53.
D. R. Borger and J. A. DeCaprio (2006)
J. Virol. 80, 4292-4303
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ATM Activation by Ionizing Radiation Requires BRCA1-associated BAAT1.
J. A. Aglipay, S. A. Martin, H. Tawara, S. W. Lee, and T. Ouchi (2006)
J. Biol. Chem. 281, 9710-9718
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Ataxia-Telangiectasia-Mutated (ATM) Protein Can Enhance Human Immunodeficiency Virus Type 1 Replication by Stimulating Rev Function.
Y. Ariumi and D. Trono (2006)
J. Virol. 80, 2445-2452
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