ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex
Abstract
The ataxia-telangiectasia mutated (ATM) kinase signals the presence of DNA double-strand breaks in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair. We show that the Mre11-Rad50-Nbs1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosphorylation of the downstream cellular targets p53 and Chk2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage.
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Molecular interaction data have been deposited in the Biomolecular Interaction Network Database (BIND) with accession codes 216020 to 216045. We thank M. Kastan and R. Abraham for expression constructs; D. Ramsden, M. Gellert, and M. O'Dea for Rag1/Rag2 protein; S. Stevens for technical advice; members of the Paull lab for their help; and R. Rothstein for a helpful word. This work was supported by NIH (grant CA094008) and by the American Cancer Society (grant RSG-04-173-01-CCG).
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Science
Volume 308 | Issue 5721
22 April 2005
22 April 2005
Copyright
American Association for the Advancement of Science.
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Submission history
Received: 6 December 2004
Accepted: 24 February 2005
Published in print: 22 April 2005
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www.sciencemag.org/cgi/content/full/1108297/DC1
Materials and Methods
Figs. S1 and S2
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- Ji-Hoon Lee,
- Tanya T. Paull
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