Two-step activation of ATM by DNA and the Mre11–Rad50–Nbs1 complex

摘要: DNA double-strand breaks (DSBs) trigger activation of the ATM protein kinase, which coordinates cell-cycle arrest, repair and apoptosis. We propose that by DSBs occurs in two steps. First, dimeric is recruited to damaged dissociates into monomers. The Mre11-Rad50-Nbs1 complex (MRN) facilitates this process tethering DNA, thereby increasing local concentration DNA. Notably, bypasses requirement for MRN, monomers generated absence MRN are not phosphorylated on Ser1981. Second, ATM-binding domain Nbs1 required sufficient convert unphosphorylated enzymatically active This model clarifies mechanism normal cells explains phenotype from patients with ataxia telangiectasia-like disorder Nijmegen breakage syndrome.