This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cerosaletti, K.
Right arrow Articles by Concannon, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cerosaletti, K.
Right arrow Articles by Concannon, P.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Yuan, J., Chen, J. (2010). MRE11-RAD50-NBS1 Complex Dictates DNA Repair Independent of H2AX. J. Biol. Chem. 285: 1097-1104 [Abstract] [Full Text]  
  • Daniel, J. A., Pellegrini, M., Lee, J.-H., Paull, T. T., Feigenbaum, L., Nussenzweig, A. (2008). Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo. JCB 183: 777-783 [Abstract] [Full Text]  
  • Stiff, T., Cerosaletti, K., Concannon, P., O'Driscoll, M., Jeggo, P. A. (2008). Replication independent ATR signalling leads to G2/M arrest requiring Nbs1, 53BP1 and MDC1. Hum Mol Genet 17: 3247-3253 [Abstract] [Full Text]  
  • Lakdawala, S. S., Schwartz, R. A., Ferenchak, K., Carson, C. T., McSharry, B. P., Wilkinson, G. W., Weitzman, M. D. (2008). Differential Requirements of the C Terminus of Nbs1 in Suppressing Adenovirus DNA Replication and Promoting Concatemer Formation. J. Virol. 82: 8362-8372 [Abstract] [Full Text]  
  • Riches, L. C., Lynch, A. M., Gooderham, N. J. (2008). Early events in the mammalian response to DNA double-strand breaks. Mutagenesis 23: 331-339 [Abstract] [Full Text]  
  • Melander, F., Bekker-Jensen, S., Falck, J., Bartek, J., Mailand, N., Lukas, J. (2008). Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage-modified chromatin. JCB 181: 213-226 [Abstract] [Full Text]  
  • Sun, Y., Xu, Y., Roy, K., Price, B. D. (2007). DNA Damage-Induced Acetylation of Lysine 3016 of ATM Activates ATM Kinase Activity. Mol. Cell. Biol. 27: 8502-8509 [Abstract] [Full Text]  
  • Cariveau, M. J., Tang, X., Cui, X.-L., Xu, B. (2007). Characterization of an NBS1 C-Terminal Peptide That Can Inhibit Ataxia Telangiectasia Mutated (ATM)-Mediated DNA Damage Responses and Enhance Radiosensitivity. Mol. Pharmacol. 72: 320-326 [Abstract] [Full Text]  
  • Difilippantonio, S., Celeste, A., Kruhlak, M. J., Lee, Y., Difilippantonio, M. J., Feigenbaum, L., Jackson, S. P., McKinnon, P. J., Nussenzweig, A. (2007). Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis. JEM 204: 1003-1011 [Abstract] [Full Text]  
  • Luo, M. H., Rosenke, K., Czornak, K., Fortunato, E. A. (2007). Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection. J. Virol. 81: 1934-1950 [Abstract] [Full Text]  
  • Buscemi, G., Carlessi, L., Zannini, L., Lisanti, S., Fontanella, E., Canevari, S., Delia, D. (2006). DNA Damage-Induced Cell Cycle Regulation and Function of Novel Chk2 Phosphoresidues. Mol. Cell. Biol. 26: 7832-7845 [Abstract] [Full Text]  
  • Ciapponi, L., Cenci, G., Gatti, M. (2006). The Drosophila Nbs Protein Functions in Multiple Pathways for the Maintenance of Genome Stability. Genetics 173: 1447-1454 [Abstract] [Full Text]  


Copyright © 2010 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»