Structure-function relationship of viral cis-acting RNA elements. The role of the ori I and ori R in enterovirus replication.
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[S.l. : s.n.]
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RU Radboud Universiteit Nijmegen, 19 juni 2007
Promotor : Galama, J.M.D. Co-promotores : Melchers, W.J.G., Kuppeveld, F.J.M. van
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SubjectUMCN 4.1: Microbial pathogenesis and host defense
The genus Enterovirus belongs to Picornaviridae, a family of small, non-enveloped, lytic RNA viruses. They contain a single-stranded RNA genome of positive polarity of approximately 7,500 nucleotides. A viral protein VPg is specifically linked to the 5'terminus of the viral RNA. IRES-mediated initiation of viral RNA translation yields a single polyprotein, which is processed to yield structural and non-structural proteins. The non-structural proteins are involved in viral RNA replication. Enterovirus RNA replication is initiated with the synthesis of a complementary negative RNA strand from virion RNA. Multiple rounds of positive-strand RNA synthesis using the negative-strand as a matrix generates a large pool of progeny RNA, which is encapsidated to produce infectious virus particles. Finally, virus progeny is released into the extracellular medium by cell- lysis. The enterovirus RNA genome contains RNA structures dubbed cis-acting replication elements, which, in concert with replication proteins, have been speculated to regulate RNA replication. The main objective of the studies described in this thesis was to obtain more insight into the functional and structural aspects of two RNA elements, the OriI and the OriR using coxsackie B3 virus as a model. The results indicated that both the OriI and the OriR form RNP complexes to execute their function. Besides encoding part of the enterovirus 2C protein the OriI also serves as the primary template for uridylylation of the peptide primer VPg, required for the initiation of both negative- and positive- strand RNA synthesis. The OriR was found to be a multifunctional RNA element involved in several important steps of the enterovirus life-cycle; i) initiation of negative-strand RNA synthesis, ii) polyadenylation of progeny RNA and iii) enterovirus pathogenicity. Multi-functionality of both the OriI and OriR indicates that the small RNA viruses use their genomes very efficiently to maximize the output of the genetic information
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