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Molecular and Cellular Biology, October 2007, p. 7028-7040, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00579-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

DNA Damage-Dependent Acetylation and Ubiquitination of H2AX Enhances Chromatin Dynamics{triangledown} ,{dagger}

Tsuyoshi Ikura,1*,{ddagger} Satoshi Tashiro,2,{ddagger} Akemi Kakino,4 Hiroki Shima,2 Naduparambil Jacob,5 Ravindra Amunugama,5 Kristine Yoder,5 Shunsuke Izumi,6 Isao Kuraoka,7 Kiyoji Tanaka,7 Hiroshi Kimura,8 Masae Ikura,1 Shuichi Nishikubo,4 Takashi Ito,9 Akihiko Muto,1 Kiyoshi Miyagawa,3 Shunichi Takeda,10 Richard Fishel,5 Kazuhiko Igarashi,1 and Kenji Kamiya4*

Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryoumachi 2-1, Aobaku Sendai 980-8575, Japan,1 Department of Cellular Biology,2 Department of Human Genetics,3 Department of Experimental Oncology, RIRBM, Hiroshima University, Hiroshima 734-8553, Japan,4 Molecular Virology, Immunology and Medical Genetics, Human Cancer Genetics, The Ohio State University School of Medicine and Public Health, Columbus, Ohio 43210,5 Graduate School of Science and The Center for Quantum Life Science, Hiroshima University, 1-3-1 Kagamiyama, Higashihiroshima 739-8526, Japan,6 Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan,7 Nuclear Function and Dynamics Unit, HMRO, School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan,8 Department of Biochemistry, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan,9 CREST Laboratory, Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan,10

Received 2 April 2007/ Returned for modification 17 May 2007/ Accepted 2 August 2007

Chromatin reorganization plays an important role in DNA repair, apoptosis, and cell cycle checkpoints. Among proteins involved in chromatin reorganization, TIP60 histone acetyltransferase has been shown to play a role in DNA repair and apoptosis. However, how TIP60 regulates chromatin reorganization in the response of human cells to DNA damage is largely unknown. Here, we show that ionizing irradiation induces TIP60 acetylation of histone H2AX, a variant form of H2A known to be phosphorylated following DNA damage. Furthermore, TIP60 regulates the ubiquitination of H2AX via the ubiquitin-conjugating enzyme UBC13, which is induced by DNA damage. This ubiquitination of H2AX requires its prior acetylation. We also demonstrate that acetylation-dependent ubiquitination by the TIP60-UBC13 complex leads to the release of H2AX from damaged chromatin. We conclude that the sequential acetylation and ubiquitination of H2AX by TIP60-UBC13 promote enhanced histone dynamics, which in turn stimulate a DNA damage response.

* Corresponding author. Mailing address for Tsuyoshi Ikura: Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryoumachi 2-1, Aobaku Sendai 980-8575, Japan. Phone: 81-022-717-7597. Fax: 81-022-717-7598. E-mail: ikurat{at}mail.tains.tohoku.ac.jp. Mailing address for Kenji Kamiya: Department of Experimental Oncology, RIRBM, Hiroshima University, Hiroshima 734-8553, Japan. Phone: 81-082-257-5842. Fax: 81-082-257-5844. E-mail: kkamiya{at}hiroshima-u.ac.jp

{triangledown} Published ahead of print on 20 August 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, October 2007, p. 7028-7040, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00579-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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