ATM is required for I kappa B kinase (IKK) activation in response to DNA double strand breaks

Following challenge with proinflammatory stimuli or generation of DNA doubl e strand breaks (DSBs), transcription factor NF-kappaB translocates from th e cytoplasm to the nucleus to activate expression of target genes. In addit ion, NF-kappaB plays a key role in protecting cells from proapoptotic stimu li, including DSBs. Patients suffering from the genetic disorder ataxia-tel angiectasia, caused by mutations in the ATM gene, are highly sensitive to i nducers of DSBs, such as ionizing radiation. Similar hypersensitivity is di splayed by cell lines derived from ataxia-telangiectasia patients or Atm kn ockout 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-kappaB deficiencies result in increa sed sensitivity to DSBs, we examined the role of ATM in NF-kappaB activatio n. We report that ATM is essential for NF-kappaB activation in response to DSBs but not proinflammatory stimuli, and this activity is mediated via the I kappaB kinase complex. DNA-dependent protein kinase, another member of t he PI3K-like family, PI3K itself, and c-Abl, a nuclear tyrosine kinase,are not required for this response.