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Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail

Tuplin, Andrew, Struthers, Madeline, Cook, Jonathan, Bentley, Kirsten and Evans, David J. 2015. Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail. Nucleic Acids Research 43 (5) , pp. 2914-2926. 10.1093/nar/gkv142

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Abstract

A phylogenetically conserved RNA structure within the NS5B coding region of hepatitis C virus functions as a cis-replicating element (CRE). Integrity of this CRE, designated SL9266 (alternatively 5BSL3.2), is critical for genome replication. SL9266 forms the core of an extended pseudoknot, designated SL9266/PK, involving long distance RNA–RNA interactions between unpaired loops of SL9266 and distal regions of the genome. Previous studies demonstrated that SL9266/PK is dynamic, with ‘open’ and ‘closed’ conformations predicted to have distinct functions during virus replication. Using a combination of site-directed mutagenesis and locked nucleic acids (LNA) complementary to defined domains of SL9266 and its interacting regions, we have explored the influence of this structure on genome translation and replication. We demonstrate that LNAs which block formation of the closed conformation inhibit genome translation. Inhibition was at least partly independent of the initiation mechanism, whether driven by homologous or heterologous internal ribosome entry sites or from a capped message. Provision of SL9266/PK in trans relieved translational inhibition, and mutational analysis implied a mechanism in which the closed conformation recruits a cellular factor that would otherwise suppresses translation. We propose that SL9266/PK functions as a temporal switch, modulating the mutually incompatible processes of translation and replication.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Oxford University Press
ISSN: 0305-1048
Date of First Compliant Deposit: 24 February 2021
Date of Acceptance: 12 February 2015
Last Modified: 24 Feb 2021 17:15
URI: https://orca.cardiff.ac.uk/id/eprint/138934

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