Owen, Thomas John (2010)
Ph.D. thesis, University of Birmingham.
The Epstein-Barr virus (EBV)-encoded RNAs (EBERs) are abundantly expressed in all EBV-associated malignancies, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression have not been fully determined. Abundant EBER expression has previously been demonstrated to be important for the oncogenic potential of the EBERs to be realised in epithelial cells. This study aimed to elucidate further how EBV achieves abundant EBER expression. Firstly, experimental analysis focussed on the possible direct correlation between EBV genomic copy number and levels of EBER expression. These initial experiments revealed that no direct link between EBV genomic copy number and levels of EBER expression was evident, suggesting that EBV may be influencing the cellular environment. Previously, EBV has been demonstrated to induce a variety of cellular EBER-associated transcription factors, and the remainder of the study focussed on determining the role of EBV nuclear antigen 1 (EBNA1) in inducing changes to the cellular environment to allow high levels of EBER expression. EBNA1 was found to induce the transcription of cellular RNA polymerase (pol) II and pol III transcription factors associated with EBER expression and levels of the cellular transcripts transcribed by the EBER-transcribing pol III were increased. Cell systems were generated which allowed EBNA1 to be expressed transiently in EBER-expressing cells, with such expression resulting in increased EBER expression, demonstrating directly that EBNA1 is able to increase levels of EBER expression. EBNA1 promoter binding studies were conducted, revealing EBNA1 to be present at the promoter regions of transcriptionally induced genes, affording mechanistic insight into EBNA1’s mode of action. The results of this study prove significant not only in determining how EBV expresses such high levels of EBERs, but also in that EBNA1 is shown to influence several cellular factors directly implicated in oncogenesis.
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