The study investigates the requirement of the MRN complex for ATM activation in response to DNA double-strand breaks (DSBs). The MRN complex, composed of Mre11, Rad50, and Nbs1, is involved in the initial processing of DSBs. ATM, a key protein kinase in the DNA damage response network, is activated by DSBs and phosphorylates various proteins. Deficiencies in ATM or components of the MRN complex lead to genetic disorders such as ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS). The authors found that functional MRN is essential for ATM activation and subsequent ATM-mediated pathways. They demonstrated that ATM activation is defective in cells with MRN deficiencies, and that the nuclear retention of ATM, a hallmark of ATM activation, is also impaired. Additionally, they showed that the MRN complex is required for the phosphorylation of ATM substrates, although some of these phosphorylations do not require Nbs1. Reconstitution of the MRN complex in cells with Mre11 deficiency restored ATM activation, suggesting that the nuclease activity of Mre11 is specifically required for this process. The findings indicate that the MRN complex plays a crucial role in the early phase of the DNA damage response, upstream of ATM, and contribute to the clinical resemblance between A-T and A-TLD.The study investigates the requirement of the MRN complex for ATM activation in response to DNA double-strand breaks (DSBs). The MRN complex, composed of Mre11, Rad50, and Nbs1, is involved in the initial processing of DSBs. ATM, a key protein kinase in the DNA damage response network, is activated by DSBs and phosphorylates various proteins. Deficiencies in ATM or components of the MRN complex lead to genetic disorders such as ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS). The authors found that functional MRN is essential for ATM activation and subsequent ATM-mediated pathways. They demonstrated that ATM activation is defective in cells with MRN deficiencies, and that the nuclear retention of ATM, a hallmark of ATM activation, is also impaired. Additionally, they showed that the MRN complex is required for the phosphorylation of ATM substrates, although some of these phosphorylations do not require Nbs1. Reconstitution of the MRN complex in cells with Mre11 deficiency restored ATM activation, suggesting that the nuclease activity of Mre11 is specifically required for this process. The findings indicate that the MRN complex plays a crucial role in the early phase of the DNA damage response, upstream of ATM, and contribute to the clinical resemblance between A-T and A-TLD.