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

Oncogene volume 32, pages 1854–1862 (2013)Cite this article

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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.

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Acknowledgements

We are grateful to Dr Yosef Shiloh for providing us with the ATM-encoding plasmid. SM was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22300317) and Naito Foundation.

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Authors and Affiliations

  1. Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan

    K Sakamoto, Y Hikiba & M Akanuma

  2. Department of Gastroenterology, University of Tokyo, Tokyo, Japan

    H Nakagawa, Y Hirata, Y Hayakawa, H Kinoshita, W Nakata, K Sakitani & R Takahashi

  3. Department of Molecular Medical Science, Laboratory of Biomedical Chemistry, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan

    H Kamata

  4. Department of Gastroenterology, Yokohama City University, Yokohama, Japan

    S Maeda

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Correspondence to S Maeda.

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Sakamoto, K., Hikiba, Y., Nakagawa, H. et al. Promotion of DNA repair by nuclear IKKβ phosphorylation of ATM in response to genotoxic stimuli. Oncogene 32, 1854–1862 (2013). https://doi.org/10.1038/onc.2012.192

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