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Molecular and Cellular Biology, March 2006, p. 1691-1699, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1691-1699.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Active Role for Nibrin in the Kinetics of Atm Activation

Karen Cerosaletti,1,2 Jocyndra Wright,1 and Patrick Concannon1,2*

Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington,1 Department of Immunology, University of Washington School of Medicine, Seattle, Washington2

Received 12 September 2005/ Returned for modification 27 September 2005/ Accepted 6 December 2005

The Atm protein kinase is central to the DNA double-strand break response in mammalian cells. After irradiation, dimeric Atm undergoes autophosphorylation at Ser 1981 and dissociates into active monomers. Atm activation is stimulated by expression of the Mre11/Rad50/nibrin complex. Previously, we showed that a C-terminal fragment of nibrin, containing binding sites for both Mre11 and Atm, was sufficient to provide this stimulatory effect in Nijmegen breakage syndrome (NBS) cells. To discriminate whether nibrin's role in Atm activation is to bind and translocate Mre11/Rad50 to the nucleus or to interact directly with Atm, we expressed an Mre11 transgene with a C-terminal NLS sequence in NBS fibroblasts. The Mre11-NLS protein complexed with Rad50, localized to the nucleus in NBS fibroblasts, and associated with chromatin. However, Atm autophosphorylation was not stimulated in cells expressing Mre11-NLS, nor were downstream Atm targets phosphorylated. To determine whether nibrin-Atm interaction is necessary to stimulate Atm activation, we expressed nibrin transgenes lacking the Atm binding domain in NBS fibroblasts. The nibrin {Delta}Atm protein interacted with Mre11/Rad50; however, Atm autophosphorylation was dramatically reduced after irradiation in NBS cells expressing the nibrin {Delta}Atm transgenes relative to wild-type nibrin. These results indicate that nibrin plays an active role in Atm activation beyond translocating Mre11/Rad50 to the nucleus and that this function requires nibrin-Atm interaction.

* Corresponding author. Mailing address: Molecular Genetics Program, Benaroya Research Institute, 1201 Ninth Ave., Seattle, WA 98101. Phone: (206) 223-6476. Fax: (206) 625-7213. E-mail: patcon{at}benaroyaresearch.org.

Molecular and Cellular Biology, March 2006, p. 1691-1699, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1691-1699.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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