ATM is Required for IκB Kinase (IKK) Activation in Response to DNA Double Strand Breaks

Following challenge with proinflammatory stimuli or generation of DNA double strand breaks (DSBs), transcription factor NF-κB translocates from the cytoplasm to the nucleus to activate expression of target genes. In addition, NF-κB plays a key role in protecting cells from proapoptotic stimuli, including DSBs. Patients suffering from the genetic disorder ataxia-telangiectasia, caused by mutations in the ATM gene, are highly sensitive to inducers of DSBs, such as ionizing radiation. Similar hypersensitivity is displayed by cell lines derived from ataxia-telangiectasia patients or Atm knockout mice. The ATM protein, a member of the phosphatidylinositol 3-kinase (PI3K)-like family, is a multifunctional protein kinase whose activity is stimulated by DSBs. As both ATM and NF-κB deficiencies result in increased sensitivity to DSBs, we examined the role of ATM in NF-κB activation. We report that ATM is essential for NF-κB activation in response to DSBs but not proinflammatory stimuli, and this activity is mediated via the IκB kinase complex. DNA-dependent protein kinase, another member of the PI3K-like family, PI3K itself, and c-Abl, a nuclear tyrosine kinase, are not required for this response.