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Possible involvement of LKB1-AMPK signaling in non-homologous end joining

Oncogene volume 33, pages 1640–1648 (2014)Cite this article

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Abstract

LKB1/STK11 is a tumor suppressor gene responsible for Peutz-Jeghers syndrome, an inherited cancer disorder associated with genome instability. The LKB1 protein functions in the regulation of cell proliferation, polarization and differentiation. Here, we suggest a role of LKB1 in non-homologous end joining (NHEJ), a major DNA double-strand break (DSB) repair pathway. LKB1 localized to DNA ends upon the generation of micro-irradiation and I-SceI endonuclease-induced DSBs. LKB1 inactivation either by RNA interference or by kinase-dead mutation compromised NHEJ-mediated DNA repair by suppressing the accumulation of BRM, a catalytic subunit of the SWI/SNF complex, at DSB sites, which promotes the recruitment of an essential NHEJ factor, KU70. AMPK2, a major substrate of LKB1 and a histone H2B kinase, was recruited to DSBs in an LKB1-dependent manner. AMPK2 depletion and a mutation of H2B that disrupted the AMPK2 phoshorylation site impaired KU70 and BRM recruitment to DSB sites. LKB1 depletion induced the formation of chromosome breaks and radials. These results suggest that LKB1-AMPK signaling controls NHEJ and contributes to genome stability.

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Acknowledgements

This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan for Scientific Research on Innovative Areas (22131006 to TK and HO; and 22131005 to AY), from the Japan Society for the Promotion of Science for Young Scientists (B) KAKENHI (23701110 to HO and 24710057 to AU) and Management Expenses Grants from the Government to the National Cancer Center. A part of this work was carried out under the Cooperative Research Project Program of the Institute of Development, Aging and Cancer, Tohoku University.

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Authors and Affiliations

  1. Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan

    A Ui, H Ogiwara & T Kohno

  2. Division of Dynamic Proteome, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    A Ui, S Kanno, R Watanabe & A Yasui

  3. Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan

    S Nakajima & A Yasui

  4. Division of Life Science, Department of Molecular and Cell Biology, Laboratory of Molecular Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan

    M Harata

  5. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    H Okayama & C C Harris

  6. Division of Multistage Carcinogenesis, National Cancer Center Research Institute, Tokyo, Japan

    J Yokota

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  1. A Ui
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Correspondence to T Kohno.

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Ui, A., Ogiwara, H., Nakajima, S. et al. Possible involvement of LKB1-AMPK signaling in non-homologous end joining. Oncogene 33, 1640–1648 (2014). https://doi.org/10.1038/onc.2013.125

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