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J. Biol. Chem., Vol. 280, Issue 9, 8156-8163, March 4, 2005

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Epstein-Barr Virus Lytic Replication Elicits ATM Checkpoint Signal Transduction While Providing an S-phase-like Cellular Environment^*

Ayumi Kudoh¶, Masatoshi Fujita||, Lumin Zhang, Noriko Shirata, Tohru Daikoku, Yutaka Sugaya, Hiroki Isomura, Yukihiro Nishiyama, and Tatsuya Tsurumi**

From the Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan, the ^||Virology Division, National Cancer Center, Chuo-ku, Tokyo 104-0045, Japan, and the Department of Virology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

When exposed to genotoxic stress, eukaryotic cells demonstrate a DNA damage response with delay or arrest of cell-cycle progression, providing time for DNA repair. Induction of the Epstein-Barr virus (EBV) lytic program elicited a cellular DNA damage response, with activation of the ataxia telangiectasia-mutated (ATM) signal transduction pathway. Activation of the ATM-Rad3-related (ATR) replication checkpoint pathway, in contrast, was minimal. The DNA damage sensor Mre11-Rad50-Nbs1 (MRN) complex and phosphorylated ATM were recruited and retained in viral replication compartments, recognizing newly synthesized viral DNAs as abnormal DNA structures. Phosphorylated p53 also became concentrated in replication compartments and physically interacted with viral BZLF1 protein. Despite the activation of ATM checkpoint signaling, p53-downstream signaling was blocked, with rather high S-phase CDK activity associated with progression of lytic infection. Therefore, although host cells activate ATM checkpoint signaling with response to the lytic viral DNA synthesis, the virus can skillfully evade this host checkpoint security system and actively promote an S-phase-like environment advantageous for viral lytic replication.

Received for publication, October 6, 2004 , and in revised form, December 15, 2004.

^* This work was supported by Grants-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, Culture and Technology of Japan (16017322 and 15390153, to T. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

^** To whom correspondence should be addressed: Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusaku, Nagoya 464-8681, Japan. Tel./Fax: 81-52-764-2979; E-mail: ttsurumi{at}aichi-cc.jp.

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