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}icmb.utexas.edu

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DNA Polymerase {eta}, the Product of the Xeroderma Pigmentosum Variant Gene and a Target of p53, Modulates the DNA Damage Checkpoint and p53 Activation.

G. Liu and X. Chen (2006)
Mol. Cell. Biol. 26, 1398-1413
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Stalled Replication Induces p53 Accumulation through Distinct Mechanisms from DNA Damage Checkpoint Pathways.

C. C. Ho, W. Y. Siu, A. Lau, W. M. Chan, T. Arooz, and R. Y.C. Poon (2006)
Cancer Res. 66, 2233-2241
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Recruitment of DNA Damage Checkpoint Proteins to Damage in Transcribed and Nontranscribed Sequences.

G. Jiang and A. Sancar (2006)
Mol. Cell. Biol. 26, 39-49
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DNA damage checkpoints in mammals.

H. Niida and M. Nakanishi (2006)
Mutagenesis 21, 3-9
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Ataxia-telangiectasia-mutated (ATM) Is a T-antigen Kinase That Controls SV40 Viral Replication in Vivo.

Y. Shi, G. E. Dodson, S. Shaikh, K. Rundell, and R. S. Tibbetts (2005)
J. Biol. Chem. 280, 40195-40200
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Evidence for the Direct Binding of Phosphorylated p53 to Sites of DNA Breaks In vivo.

S. T. Al Rashid, G. Dellaire, A. Cuddihy, F. Jalali, M. Vaid, C. Coackley, M. Folkard, Y. Xu, B. P.C. Chen, D. J. Chen, et al. (2005)
Cancer Res. 65, 10810-10821
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Protein Phosphatase 5 Is Required for ATR-Mediated Checkpoint Activation.

J. Zhang, S. Bao, R. Furumai, K. S. Kucera, A. Ali, N. M. Dean, and X.-F. Wang (2005)
Mol. Cell. Biol. 25, 9910-9919
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Rad50 depletion impacts upon ATR-dependent DNA damage responses.

H. Zhong, A. Bryson, M. Eckersdorff, and D. O. Ferguson (2005)
Hum. Mol. Genet. 14, 2685-2693
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A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM.

Y. Sun, X. Jiang, S. Chen, N. Fernandes, and B. D. Price (2005)
PNAS 102, 13182-13187
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Independent and sequential recruitment of NHEJ and HR factors to DNA damage sites in mammalian cells.

J.-S. Kim, T. B. Krasieva, H. Kurumizaka, D. J. Chen, A. M. R. Taylor, and K. Yokomori (2005)
J. Cell Biol. 170, 341-347
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Identification of Domains of Ataxia-telangiectasia Mutated Required for Nuclear Localization and Chromatin Association.

D. B. Young, J. Jonnalagadda, M. Gatei, D. A. Jans, S. Meyn, and K. K. Khanna (2005)
J. Biol. Chem. 280, 27587-27594
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