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 mouse cells containing targeted mutant alleles of Mre11 (Mre11a) and/or Ku70 (Xrcc6), together with pharmacologic kinase inhibition, we demonstrate that ATM can be activated by DSBs in the absence of MRN. When MRN is deficient, DNA-PKcs efficiently substitutes for ATM in facilitating local chromatin responses. In the absence of both MRN and Ku, ATM is recruited to chromatin, where it phosphorylates H2AX and triggers the G2-M cell-cycle checkpoint, but the DNA-repair functions of MRN are not restored. These results suggest that, in contrast to straightforward recruitment and activation by MRN, a complex interplay between sensors has a substantial role in ATM control.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Andrea J
AJ
Hartlerode
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Mary J
MJ
Morgan
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Yipin
Y
Wu
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jeffrey
J
Buis
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
David O
DO
Ferguson
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D051379:Mice; D011485:Protein Binding
D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse