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Journal of Virology, June 2007, p. 6718-6730, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00053-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The ATM/ATR Signaling Effector Chk2 Is Targeted by Epstein-Barr Virus Nuclear Antigen 3C To Release the G₂/M Cell Cycle Block

Tathagata Choudhuri, Subhash C. Verma, Ke Lan, Masanao Murakami, and Erle S. Robertson^*

Department of Microbiology and The Tumor Virology Program of the Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Received 9 January 2007/ Accepted 27 March 2007

Epstein-Barr virus (EBV) infects most of the human population and persists in B lymphocytes for the lifetime of the host. The establishment of latent infection by EBV requires the expression of a unique repertoire of genes. The product of one of these viral genes, the EBV nuclear antigen 3C (EBNA3C), is essential for the growth transformation of primary B lymphocytes in vitro and can regulate the transcription of a number of viral and cellular genes important for the immortalization process. This study demonstrates an associated function of EBNA3C which involves the disruption of the G₂/M cell cycle checkpoint. We show that EBNA3C-expressing lymphoblastoid cell lines treated with the drug nocodazole, which is known to block cells at the G₂/M transition, did not show a G₂/M-specific checkpoint arrest. Analyses of the cell cycles of cells expressing EBNA3C demonstrated that the expression of this essential EBV nuclear antigen is capable of releasing the G₂/M checkpoint arrest induced by nocodazole. This G₂/M arrest in response to nocodazole was also abolished by caffeine, suggesting an involvement of the ATM/ATR signaling pathway in the regulation of this cell cycle checkpoint. Importantly, we show that the direct interaction of EBNA3C with Chk2, the ATM/ATR signaling effector, is responsible for the release of this nocodazole-induced G₂/M arrest and that this interaction leads to the serine 216 phosphorylation of Cdc25c, which is sequestered in the cytoplasm by 14-3-3. Overall, our data suggest that EBNA3C can directly regulate the G₂/M component of the host cell cycle machinery, allowing for the release of the checkpoint block.

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* Corresponding author. Mailing address: Department of Microbiology and Abramson Comprehensive Cancer Center, University of Pennsylvania School of Medicine, 201E Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104. Phone: (215) 746-0116. Fax: (215) 898-9557. E-mail: erle{at}mail.med.upenn.edu

Published ahead of print on 4 April 2007.

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Journal of Virology, June 2007, p. 6718-6730, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00053-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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