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Journal of Virology, August 2009, p. 8090-8098, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.02379-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Topoisomerase I and RecQL1 Function in Epstein-Barr Virus Lytic Reactivation{triangledown}

Pu Wang,1 Andrew J. Rennekamp,1 Yan Yuan,2 and Paul M. Lieberman1*

The Wistar Institute, Philadelphia, Pennsylvania 19104,1 Department of Microbiology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania2

Received 17 November 2008/ Accepted 27 May 2009

Cellular topoisomerases and helicases are thought to play an essential role in herpesvirus replication and gene expression and are considered to be potential targets for antiviral therapies. Topoisomerase I (Topo I) and Topo II inhibitors can selectively inhibit Epstein-Barr virus (EBV) lytic cycle DNA replication. We found that the Topo I inhibitor camptothecin and, to a lesser extent, the Topo II inhibitor etoposide are potent inhibitors of the transcription and replication function of the EBV-encoded immediate-early protein Zta (also referred to as ZEBRA, EB1, and BZLF1). Camptothecin inhibited the Zta transcription activation of endogenous and reporter-linked viral promoters. Small interfering RNA depletion of Topo I also inhibited the Zta-dependent activation of lytic cycle DNA replication. Topo I could be coimmunoprecipitated with Zta, but this interaction was restricted to EBV-positive cells, suggesting that other viral proteins stabilize the interaction between Zta and Topo I. We also found that the RecQL1 helicase, which is known to associate with Kaposi's sarcoma-associated herpesvirus (KSHV) OriLyt, interacts with EBV OriLyt. Treatment with camptothecin reduced both Zta and RecQL1 binding to OriLyt in vivo, suggesting that Topo I promotes replication protein assembly at OriLyt.

* Corresponding author. Mailing address: the Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: (215) 898-9491. Fax: (215) 898-0663. E-mail: lieberman{at}wistar.org

{triangledown} Published ahead of print on 3 June 2009.

Journal of Virology, August 2009, p. 8090-8098, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.02379-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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