title: Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Hikiba
authors.forename: H
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hirata
authors.forename: Y
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: H
authors.initials: H
authors.lastname: Kinoshita
authors.forename: W
authors.initials: W
authors.lastname: Nakata
authors.forename: K
authors.initials: K
authors.lastname: Sakitani
authors.forename: R
authors.initials: R
authors.lastname: Takahashi
authors.forename: M
authors.initials: M
authors.lastname: Akanuma
authors.forename: H
authors.initials: H
authors.lastname: Kamata
authors.forename: S
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D020552:Comet Assay; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase