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Journal of Virology, March 2009, p. 2154-2162, Vol. 83, No. 5
0022-538X/09/$08.00+0     doi:10.1128/JVI.02115-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Episome Stability Is Coupled to a Delay in Replication Timing {triangledown} ,{dagger}

Jing Zhou, Andrew R. Snyder, and Paul M. Lieberman*

The Wistar Institute, Philadelphia, Pennsylvania 19104

Received 7 October 2008/ Accepted 3 December 2008

The temporal regulation of DNA replication is thought to be important for chromosome organization and genome stability. We show here that Epstein-Barr virus (EBV) genomes replicate in mid- to late S phase and that agents that accelerate replication timing of EBV reduce viral genome stability. Hydroxyurea (HU) treatment, which is known to eliminate EBV episomes, shifted EBV replication to earlier times in the cell cycle. HU treatment correlated with hyperacetylation of histone H3 and loss of telomere repeat factor 2 (TRF2) binding at the EBV origin of plasmid replication (OriP). Deletion of TRF2 binding sites within OriP or short hairpin RNA depletion of TRF2 advanced the replication timing of OriP-containing plasmids. Inhibitors of class I histone deacetylases (HDACs) increased histone acetylation at OriP, advanced the replication timing of EBV, and reduced EBV genome copy number. We also show that HDAC1 and -2 form a stable complex with TRF2 at OriP and that HU treatment inhibits HDAC activity. We propose that the TRF2-HDAC complex enhances EBV episome stability by providing a checkpoint that delays replication initiation at OriP.

* Corresponding author. Mailing address: The Wistar Institute, Philadelphia, PA 19104. Phone: (215) 898-9491. Fax: (215) 898-0663. E-mail: Lieberman{at}wistar.org

{triangledown} Published ahead of print on 10 December 2008.

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

Journal of Virology, March 2009, p. 2154-2162, Vol. 83, No. 5
0022-538X/09/$08.00+0     doi:10.1128/JVI.02115-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Wang, S., Frappier, L. (2009). Nucleosome Assembly Proteins Bind to Epstein-Barr Virus Nuclear Antigen 1 and Affect Its Functions in DNA Replication and Transcriptional Activation. J. Virol. 83: 11704-11714 [Abstract] [Full Text]  


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