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J. Virol. 87 (1): 208-223

Copyright © 2013 by the American Society for Microbiology. All rights reserved.

Essential Role of Rta in Lytic DNA Replication of Epstein-Barr Virus

Ayman El-Guindy,a,e Maryam Ghiassi-Nejad,a Sean Golden,d Henri-Jacques Delecluse,f, and George Millera,b,c,e

Departments of Pediatrics,a Molecular Biophysics and Biochemistry,b Epidemiology and Public Health,c Molecular Cellular and Developmental Biology,d Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA,e German Cancer Research Centre, DKFZ, Pathology of Virus-Associated Tumors, Heidelberg, Germany,f

Received for publication 6 August 2012. Accepted for publication 20 September 2012.

Abstract: Two transcription factors, ZEBRA and Rta, switch Epstein-Barr virus (EBV) from the latent to the lytic state. While ZEBRA also plays an obligatory role as an activator of replication, it is not known whether Rta is directly required for replication. Rta is dispensable for amplification of an oriLyt-containing plasmid in a transient-replication assay. Here, we assessed the requirement for Rta in activation of viral DNA synthesis from the endogenous viral genome, a function that has not been established. Initially, we searched for a ZEBRA mutant that supports viral replication but not transcription. We found that Z(S186A), a mutant of ZEBRA unable to activate transcription of Rta or viral genes encoding replication proteins, is competent to bind to oriLyt and to function as an origin recognition protein. Ectopic expression of the six components of the EBV lytic replication machinery failed to rescue replication by Z(S186A). However, addition of Rta to Z(S186A) and the mixture of replication factors activated viral replication and late gene expression. Deletion mutagenesis of Rta indicated that the C-terminal 10 amino acids (aa) were essential for the function of Rta in replication. In vivo DNA binding studies revealed that Rta interacted with the enhancer region of oriLyt. In addition, expression of Rta and Z(S186A) together, but not individually, activated synthesis of the BHLF1 transcript, a lytic transcript required for the process of viral DNA replication. Our findings demonstrate that Rta plays an indispensable role in the process of lytic DNA replication.

Address correspondence to Ayman El-Guindy, ayman.el-guindy{at}

Published ahead of print 17 October 2012

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S. Omoto and E. S. Mocarski (2013)
J. Virol. 87, 8651-8664
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Latency of Epstein-Barr virus is disrupted by gain-of-function mutant cellular AP-1 proteins that preferentially bind methylated DNA.
K.-P. Yu, L. Heston, R. Park, Z. Ding, R. Wang'ondu, H.-J. Delecluse, and G. Miller (2013)
PNAS 110, 8176-8181
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