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ATM-mediated KDM2A phosphorylation is required for the DNA damage repair

Oncogene volume 35, pages 301–313 (2016)Cite this article

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A Corrigendum to this article was published on 21 January 2016

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Abstract

The ataxia-telangiectasia mutated (ATM) protein is a key signaling molecule that modulates the DNA damage response. However, the exact mechanism by which ATM regulates DNA damage repair has not yet been elucidated. Here, we report that ATM regulates the DNA damage response by phosphorylating lysine-specific demethylase 2A (KDM2A), a histone demethylase that acts at sites of H3K36 dimethylation. ATM interacts with KDM2A, and their interaction significantly increases in response to DNA double-stranded, but not single-stranded, breaks. ATM specifically phosphorylates KDM2A at threonine 632 (T632) following DNA damage, as demonstrated by a mutagenesis assay and mass spectrometric analysis. Although KDM2A phosphorylation does not alter its own demethylase activity, T632 phosphorylation of KDM2A largely abrogates its chromatin-binding capacity, and H3K36 dimethylation near DNA damage sites is significantly increased. Consequently, enriched H3K36 dimethylation serves as a platform to recruit the MRE11 complex to DNA damage sites by directly interacting with the BRCT2 domain of NBS1, which results in efficient DNA damage repair and enhanced cell survival. Collectively, our study reveals a novel mechanism for ATM in connecting histone modifications with the DNA damage response.

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  • 21 January 2016

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue.

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Acknowledgements

We thank Dr David J Chen at University of Texas Southwestern Medical Center for kindly providing YFP-ATM plasmid. We also thank Drs Jun Huang at Zhejiang University and Jiadong Wang at Peking University Health Science Center for kindly providing NBS1 deleted mutants. This work was supported by National Key Basic Research Program of China grant 2011CB504200, 2013CB911000; National Natural Science Foundation of China grants 31070691, 81321003, 91319302; Minister of Education of China ‘111 Project’.

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Author notes

  1. L-L Cao and F Wei: These authors contributed equally to this work.

  2. Professor W-G Zhu, Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Xueyuan Road 38#, Beijing, 100191, China. E-mail: zhuweiguo@bjmu.edu.cn

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China

    L-L Cao, F Wei, Y Du, B Song, D Wang, C Shen, X Lu, Z Cao, Q Yang, L Wang, Y Zhao, H Wang, Y Yang & W-G Zhu

  2. Protein Chemistry Facility, School of Biological Sciences, Tsinghua University, Beijing, China

    Y Gao

  3. Peking University-Tsinghua University Joint Center for Life Sciences, Beijing, China

    W-G Zhu

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Cao, LL., Wei, F., Du, Y. et al. ATM-mediated KDM2A phosphorylation is required for the DNA damage repair. Oncogene 35, 301–313 (2016). https://doi.org/10.1038/onc.2015.81

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