Science · 2005 · 1.4K citations · 17 references
Life SciencesGeneticsMolecular BiologyApoptosisDna RepairMolecular OncologyDna DamageDna Damage SignalingDna Damage-induced ApoptosisDna Double-strand Break RepairDna Strand BreaksDouble-strand Break RepairAtm ActivationDna Damage Checkpoint ActivationDna Damage Response SignalingDna Damage SensingDna Damage SensorsDna Double-strand BreaksDouble-strand Dna BreaksMrn Complex Function
ATM kinase signals DNA double‑strand breaks by phosphorylating proteins that trigger cell‑cycle arrest, apoptosis, and repair. The Mre11‑Rad50‑Nbs1 complex senses double‑strand breaks, recruits and activates ATM without requiring ATM autophosphorylation, and its DNA‑unwinding activity is essential for stimulating ATM‑mediated phosphorylation of p53 and Chk2.
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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Requirement of the MRN complex for ATM activation by DNA damage
Tamar Uziel, Yaniv Lerenthal, Lilach Moyal et al. · The EMBO Journal · 2003 · 1.1K citations · Full text
Choreography of the DNA Damage Response
Michael Lisby, Jacqueline H. Barlow, Rebecca C. Burgess et al. · Cell · 2004 · 891 citations · Full text