Recruitment and activation of the ATM kinase in the absence of DNA damage sensors

Two kinases, ATM and DNA-PKcs, control rapid responses to DNA double-strand breaks (DSBs). The paradigm for ATM control is recruitment and activation by the Mre11–Rad50–NBS1 (MRN) sensor complex, whereas DNA-PKcs requires the sensor Ku (Ku70–Ku80). Using Mus musculus cells harboring targeted mutant alleles of Mre11 and/or Ku70, together with pharmacologic kinase inhibition we demonstrate that ATM can in fact be activated by DSBs in the absence of MRN. When MRN is deficient, DNA-PKcs efficiently substitutes for ATM in facilitating local chromatin responses. Strikingly, in the absence of both MRN and Ku, ATM is recruited to chromatin, phosphorylates H2AX, and triggers the G2/M cell cycle checkpoint, but DNA repair functions of MRN are not restored. This implies that a complex interplay between sensors plays a significant role in ATM control, rather than straightforward recruitment and activation by MRN.