Essential transcription regulator Rta of Epstein-Barr virus - functional and structural implications for new antiviral strategy
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| Year of publication | 2022 |
| Type | Conference abstract |
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| Description |
The Epstein-Barr virus (EBV) is one of the most common human viruses that infects more than 90% of the world population during their lifetime. EBV causes 200,000 cancer cases per year and is associated with various premalignant lymphoproliferative diseases, including Hodgkin's lymphoma, gastric cancer, and nasopharyngeal carcinoma [1]. Besides cancer, infectious mononucleosis and multiple sclerosis are linked to EBV [2, 3]. The Replication and transcription activator (Rta) can activate the lytic phase of EBV from its latency and is therefore essential for the EBV life cycle. As a transcription regulator, Rta binds to Rta Response Element (RRE) localized on viral DNA and transactivates a series of lytic genes, including the viral lytic gene PAN [4]. Rta has not been structurally characterized yet, and no direct homologies were identified compared to other known DNA binding or dimerization motifs [5]. Here, we present an interdisciplinary study of Rta function. We characterized the biophysical properties of the DNA binding domain of Rta and its oligomerization, which is crucial for DNA binding. Moreover, we described the structural features of the DNA binding domain of Rta. We determined the binding affinity of Rta towards a specific DNA sequence containing the RRE motif. In parallel with an in vitro study, we characterized Rta in a human cancer cell line, where we investigated Rta nuclear localization and its sequestration from nucleoli. Rta targeting with small molecules presents a new potential approach in the fight against EBV-associated diseases. Thus, a detailed understanding of the Rta structure and oligomeric state is critical for future rational anti-EBV drug design. 1. Rezk S.A, et al., Human Pathology, 79, (2018), 18-41. 2. Williams H., et al., Blood, 107 (2006), 862–869. 3. Bjornevik, K., et al., Science, 375, (2022), 296-301. 4. Feederle R., and Delecluse H., The EMBO Journal, 19, (2000), 3080-3089. 5. Necasova I., et al., NAR Cancer, 4, (2022) |
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