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Molecular and Cellular Biology, February 2000, p. 1344-1360, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Epstein-Barr Virus Suppresses a G2/M Checkpoint Activated by Genotoxins

Mark Wade and Martin J. Allday*

Section of Virology and Cell Biology and Ludwig Institute for Cancer Research, Imperial College of Science Technology and Medicine, London W2 1PG, United Kingdom

Received 19 July 1999/Returned for modification 9 September 1999/Accepted 9 November 1999

Several Epstein-Barr virus (EBV)-negative Burkitt lymphoma-derived cell lines (for example, BL41 and Ramos) are extremely sensitive to genotoxic drugs despite being functionally null for the tumor suppressor p53. They rapidly undergo apoptosis, largely from G2/M of the cell cycle. 5-Bromo-2'-deoxyuridine labeling experiments showed that although the treated cells can pass through S phase, they are unable to complete cell division, suggesting that a G2/M checkpoint is activated. Surprisingly, latent infection of these genotoxin-sensitive cells with EBV protects them from both apoptosis and cell cycle arrest, allowing them to complete the division cycle. However, a comparison with EBV-immortalized B-lymphoblastoid cell lines (which have functional p53) showed that EBV does not block apoptosis per se but rather abrogates the activation of, or signalling from, the checkpoint in G2/M. Furthermore, analyses of BL41 and Ramos cells latently infected with P3HR1 mutant virus, which expresses only a subset of the latent viral genes, showed that LMP-1, the main antiapoptotic latent protein encoded by EBV, is not involved in the protection afforded here by viral infection. This conclusion was confirmed by analysis of clones of BL41 stably expressing LMP-1 from a transfected plasmid, which respond like the parental cell line. Although steady-state levels of Bcl-2 and related proteins varied between BL41 lines and clones, they did not change significantly during apoptosis, nor was the level of any of these anti- or proapoptotic proteins predictive of the outcome of treatment. We have demonstrated that a subset of EBV latent gene products can inactivate a cell cycle checkpoint for monitoring the fidelity and timing of cell division and therefore genomic integrity. This is likely to be important in EBV-associated growth transformation of B cells and perhaps tumorigenesis. Furthermore, this study suggests that EBV will be a unique tool for investigating the intimate relationship between cell cycle regulation and apoptosis.

* Corresponding author. Mailing address: Section of Virology and Cell Biology, and Ludwig Institute for Cancer Research, Imperial College of Science Technology and Medicine, St. Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom. Phone: 0171 724 5522. Fax: 0171 724 8586. E-mail: m.allday{at}ic.ac.uk.

Molecular and Cellular Biology, February 2000, p. 1344-1360, Vol. 20, No. 4
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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