Importance of PIKKs in NF-κB activation by genotoxic stress

Alteration of the genome integrity leads to the activation of a vast network of cellular responses named DNA damage response. Three kinases from the phosphoinositide 3-kinase-like protein kinase family regulate this network; ATM and DNA-PM both activated by DNA double-strand breaks and ATR activated by replication blocks. DNA damage response pathway coordinates cell cycle arrest, DNA repair, and the activation of transcription factors such as p53 and NF-kappa B. It controls senescence/apoptosis/survival of the damaged cells. Cell death or survival result from a tightly regulated balance between antagonist pro- and anti-apoptotic signals. NF-kappa B is a key transcription factor involved in immunity, inflammation and cell transformation. When activated by DNA double-strand breaks, NF-kappa B has most often a pro-survival effect and thereof interferes with chemotherapy treatments that often rely on DNA damage to induce tumor cell death (i.e. topoisomerase inhibitors and ionizing radiation). NF-kappa B is thus an important pharmaceutical target. Agents leading to replication stress induce a pro-apoptotic NF-kappa B. The molecular mechanisms initiated by DNA lesions leading to NF-kappa B nuclear translocation have been extensively studied these last years. In this review, we will focus on ATM, ATR and DNA-PK functions both in the IKK alpha/IKK beta/NEMO-dependent or -independent signaling pathways and on the regulation they can exercise at the promoter level of NF-kappa B regulated genes. (C) 2011 Elsevier Inc. All rights reserved.