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Title: Investigating the role of Epstein-Barr virus lytic key regulator protein Zta in transcriptional regulation
Author: Almohammed, Rajaei
ISNI:       0000 0004 6062 3613
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2017
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Epstein-Barr virus (EBV) is a human herpes virus that, upon primary infection, establishes life-long persistence in B cells (latency). One viral protein, the immediate early lytic protein Zta (also known as BZLF1, ZEBRA, EB1, and Z) plays a significant role in disturbing this latency and inducing a viral productive (lytic) cycle. Expression of Zta, a basic leucine zipper transcription factor, induces a cascade of viral lytic cycle gene expression. The activation of many lytic genes requires the direct binding of Zta to its response elements (ZREs) within proximal promoters of these genes. Much research in recent years has focused on investigating Zta reactivation of latency and its role in lytic viral DNA replication. This has revealed a wealth of knowledge about Zta as a multifunctional transcription factor. However, a complete understanding of Zta transcriptional activation is still missing. Here, utilising ChIP-qPCR, we showed conserved binding patterns for Zta across several EBV lytic gene promoters in two different EBV systems including a non-B cell EBV-infected cell line. Also, using luciferase reporter assays, we show the first functional evidence for a possible role of Zta in controlling transcription regulation at distal regulatory elements (enhancers). Importantly, we identified BNLF2a, an essential viral immune evasion gene, as a direct target for Zta. We identified five ZREs and mapped functional ones within the BNLF2a promoter using mutational analysis and luciferase reporter assays. We also expressed and purified a recombinant GFP-bZIP Zta protein to address Zta binding to BNLF2a ZREs in vitro. Interestingly, using in silico approach, we also identified a conserved sequence in the ZRE flanking region of all five ZREs within BNLF2a promoter and uncovered a role for a possible repressor at ZRE2 flanking region. Our work not only adds to our understanding of Zta transcription regulation but characterises for the first time the regulation of a novel Zta target that has a role in evading the host immune system during EBV pre-latency and lytic cycle.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR0355 Virology