Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli

• Published in: Oncogene Vol. 32; no. 14; pp. 1854 - 1862
• Main Authors: Sakamoto, K, Hikiba, Y, Nakagawa, H, Hirata, Y, Hayakawa, Y, Kinoshita, H, Nakata, W, Sakitani, K, Takahashi, R, Akanuma, M, Kamata, H, Maeda, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.04.2013; Nature Publishing Group
• Subjects: 631/337/1427; 631/67; Alkylating agents; Animals; Apoptosis; Ataxia; Ataxia Telangiectasia Mutated Proteins; Cell Biology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Nucleus - metabolism; Cell survival; Cells, Cultured; Cercopithecus aethiops; Comet Assay; COS Cells; Cytoplasm; Cytoplasm - metabolism; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; Genetic aspects; Genotoxicity; HeLa Cells; Homeostasis; Human Genetics; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; IKK protein; Immunoblotting; Internal Medicine; Kinases; Medicine; Medicine & Public Health; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Oncology; original-article; Phosphorylation; Physiological aspects; Protein kinases; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; RNA, Small Interfering - genetics; Signal Transduction; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Transcription factors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Japan; NF-κB; ATM; IKKβ; DNA damage
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2012.192

Ataxia-telangiectasia mutated (ATM) is one of the key molecules involved in the cellular response to DNA damage. A portion of activated ATM is exported from the nucleus into the cytoplasm, where it activates the I kappa B kinase/nuclear factor kappa B (IKK/NF-κB) signaling pathway. It has been thought that activated IKKβ, which is a critical kinase for NF-κB activation, generally resides in the cytoplasm and phosphorylates cytoplasmic downstream molecules, such as IκBα. Here, we identified a new role for IKKβ during the response to DNA damage. ATM phosphorylation in response to alkylating agents consisted of two phases: the early phase (up to 3 h) and late phase (after 6 h). A portion of the activated IKKβ generated during the DNA damage response was found to translocate into the nucleus and directly phosphorylate ATM in the late phase. Furthermore, the phosphorylation of ATM by nuclear IKKβ was suggested to promote DNA repair. In parallel, activated IKKβ induced classical NF-κB activation and was involved in anti-apoptosis. Our findings define the function of IKKβ during the response to DNA damage, which promotes cell survival and DNA repair, and maintains cellular homeostasis.