title: Importance of PIKKs in NF-κB activation by genotoxic stress.
abstract: 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-PK 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-κB. 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-κB is a key transcription factor involved in immunity, inflammation and cell transformation. When activated by DNA double-strand breaks, NF-κB 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-κB is thus an important pharmaceutical target. Agents leading to replication stress induce a pro-apoptotic NF-κB. The molecular mechanisms initiated by DNA lesions leading to NF-κB 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 IKKα/IKKβ/NEMO-dependent or -independent signaling pathways and on the regulation they can exercise at the promoter level of NF-κB regulated genes.
authors.affiliation: Laboratory of Immunology and Virology, GIGA-R, Building B34, Unit of Signal Transduction, University de Liège, 1 Allée de l'Hôpital, B-4000, Liège, Belgium.
authors.forename: Hélène
authors.initials: H
authors.lastname: Sabatel
authors.forename: Céline
authors.initials: C
authors.lastname: Pirlot
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
authors.forename: Yvette
authors.initials: Y
authors.lastname: Habraken
mesh_terms: D017209:Apoptosis / Q000502:physiology; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D058539:Phosphatidylinositol 3-Kinase