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Journal of Virology, February 1999, p. 1195-1204, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Intron Retention May Regulate Expression of Epstein-Barr Virus Nuclear Antigen 3 Family Genes

Norbert Kienzle,* David B. Young,dagger Daphne Liaskou, Marion Buck, Sonia Greco, and Tom B. Sculley

EBV Unit, The Queensland Institute of Medical Research and University of Queensland Joint Oncology Program, Brisbane, Australia

Received 4 September 1998/Accepted 26 October 1998

The nuclear antigen 3 family genes (EBNA-3, EBNA-4, and EBNA-6) of Epstein-Barr virus (EBV) are important for EBV-induced immortalization and survival of B lymphocytes. However, little is known about how the expression of these genes is regulated. Each of the EBNA-3, EBNA-4, and EBNA-6 genes consists of two exons separated by a small intron. Reverse transcriptase PCR assays revealed that the vast majority of the EBNA-3, EBNA-4, and EBNA-6 mRNA, expressed in transfected and EBV-infected B cells, retained intron sequences. Northern blot and S1 protection assays confirmed that most of the EBNA-3 mRNA contained intron. Examination of deletion mutants of EBNA-3 indicated that the EBNA-3 protein was not necessary for intron retention and that there was no splicing silencing element encoded in the EBNA-3 mRNA. Cell fractionation and RNA gradient analysis revealed that the unspliced EBNA 3 family mRNAs were transported into the cytoplasm and associated with the polysomes. However, Western blot analysis of FLAG-epitope tagged EBNA-3 gave no indication of the presence of splice variant protein forms of EBNA-3. In contrast, transiently transfected cells expressing EBNA-3 revealed a sixfold increase in EBNA-3 protein expression from the genomic EBNA-3 gene compared to EBNA-3 cDNA. These data show that the intronic sequences can influence EBNA-3 protein expression and suggest that intron retention may provide a means for the fine-tuning of expression of the individual EBNA 3 family genes.

* Corresponding author. Mailing address: The Queensland Institute of Medical Research, Post Office, Royal Brisbane Hospital, Brisbane 4029, Queensland, Australia. Phone: 61-7-33620349. Fax: 61-7-33620106. E-mail: norbertK{at}qimr.edu.au.

dagger Present address: Johns Hopkins Medical School, Baltimore, MD 21205.

Journal of Virology, February 1999, p. 1195-1204, Vol. 73, No. 2
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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