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ATM Activation by DNA Double-Strand Breaks Through the Mre11-Rad50-Nbs1 Complex
Ji-Hoon Lee and
Tanya T. Paull*
The ataxia-telangiectasia mutated (ATM) kinase signals the presenceof DNA double-strand breaks in mammalian cells by phosphorylatingproteins that initiate cell-cycle arrest, apoptosis, and DNArepair. We show that the Mre11-Rad50-Nbs1 (MRN) complex actsas a double-strand break sensor for ATM and recruits ATM tobroken DNA molecules. Inactive ATM dimers were activated invitro with DNA in the presence of MRN, leading to phosphorylationof the downstream cellular targets p53 and Chk2. ATM autophosphorylationwas not required for monomerization of ATM by MRN. The unwindingof DNA ends by MRN was essential for ATM stimulation, whichis consistent with the central role of single-stranded DNA asan evolutionarily conserved signal for DNA damage.
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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