ATM Activation by DNA Double-Strand Breaks through the Mre11-Rad50-Nbs1 Complex

• Published in: Science (American Association for the Advancement of Science) Vol. 308; no. 5721; pp. 551 - 554
• Main Authors: Lee, Ji-Hoon, Paull, Tanya T.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 22.04.2005; The American Association for the Advancement of Science
• Subjects: Acid Anhydride Hydrolases; Amino Acid Substitution; Antibodies; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cells; Cells (Biology); Cellular biology; Deoxyribonucleic acid; Dimerization; Dimers; DNA; DNA - chemistry; DNA - metabolism; DNA Damage; DNA Repair; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; DNA, Single-Stranded - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Genomes; Humans; Mammals; Molecular and cellular biology; Molecular biology; Monomers; MRE11 Homologue Protein; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleic Acid Conformation; Phosphorylation; Plasmids; Protein Binding; Protein Serine-Threonine Kinases - chemistry; Protein Serine-Threonine Kinases - metabolism; Proteins; Recombinant Proteins - metabolism; Sequencing; Serine; Signal Transduction; Soil samples; Transfection; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism; United States; Double strand break; Double stranded DNA; Regulation(control); Enzyme; Protein kinase; Transferases; Cell cycle; Ataxia telangiectasia; Activation; Repair; Apoptosis; Genetic disease
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1108297

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.