title: Topoisomerase I and RecQL1 function in Epstein-Barr virus lytic reactivation.
abstract: 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.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rennekamp
authors.forename: Yan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Paul M
authors.initials: PM
authors.lastname: Lieberman
mesh_terms: D002460:Cell Line; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism*; D020031:Epstein-Barr Virus Infections / Q000201:enzymology* / Q000378:metabolism / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011485:Protein Binding; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014775:Virus Activation; D014779:Virus Replication
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D015534:Trans-Activators; D014764:Viral Proteins; D053484:RecQ Helicases; D004264:DNA Topoisomerases, Type I