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J. Biol. Chem., Vol. 279, Issue 37, 38813-38819, September 10, 2004

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Independent Roles for Nibrin and Mre11-Rad50 in the Activation and Function of Atm^*

Karen Cerosaletti and Patrick Concannon¶

From the Molecular Genetics Program, Benaroya Research Institute at Virginia Mason and the Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98101

The Atm protein kinase and Mre11-Rad50-nibrin (MRN) complex play an integral role in the cellular response to DNA double-strand breaks. Mutations in Mre11 and nibrin result in the radiosensitivity disorders ataxia-telangiectasia-like disorder (ATLD) and Nijmegen breakage syndrome (NBS), respectively. Cells from ATLD and NBS patients are deficient in activation of the Atm protein kinase and phosphorylation of downstream Atm targets following irradiation. However, the roles of individual MRN complex proteins in Atm function are not clear, because the mutations in NBS and ATLD cells result in global effects on the MRN complex. Previously we showed that the C-terminal 100 amino acids of nibrin were necessary and sufficient to translocate the MRN complex to the nucleus. Here we have taken advantage of this feature of nibrin to create isogenic cell lines lacking either nibrin or Mre11-Rad50 in the nucleus. We found that nuclear expression of Mre11-Rad50, but not nibrin, stimulated Atm activation at early times after low doses of radiation. At later times or higher doses of irradiation, Atm activation was independent of Mre11-Rad50 or nibrin. The requirement of MRN complex proteins for downstream Atm phosphorylation events following irradiation was more complex. Phosphorylation of nibrin and Chk2 by Atm required Mre11-Rad50 expression in the nucleus at early times after irradiation, reflecting the stimulation of Atm activation by Mre11-Rad50. By contrast, autophosphorylation of Chk2 and phosphorylation of Smc1 at Ser-957 was dependent on the MRN complex 60 min after irradiation, even though Atm was activated at that time point. These results indicate an independent role for Mre11-Rad50 in the activation of Atm and suggest nibrin and/or Mre11-Rad50 also act as adaptors for some downstream Atm phosphorylation events.

Received for publication, April 19, 2004 , and in revised form, June 29, 2004.

^* This work was supported by a grant from the A-T Medical Research Foundation (to K. C.) and NCI Grant CA57569 from the National Institutes of Health (to P. 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.

^¶ To whom correspondence should be addressed: Molecular Genetics Program, Benaroya Research Institute, 1201 Ninth Ave., Seattle, WA 98101-2795. Tel.: 206-223-6476; Fax: 206-625-7213; E-mail: patcon{at}benaroyaresearch.org.

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