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

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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, Madeleine; Cook, Jonathan; Bentley, Kirsten; Evans, David J.

In: Nucleic Acids Research, Vol. 43, No. 5, 11.03.2015, p. 2914-2926.

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Tuplin, A, Struthers, M, Cook, J, Bentley, K & Evans, DJ 2015, 'Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail' Nucleic Acids Research, vol. 43, no. 5, pp. 2914-2926. https://doi.org/10.1093/nar/gkv142

APA

Tuplin, A., Struthers, M., Cook, J., Bentley, K., & Evans, D. 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), 2914-2926. https://doi.org/10.1093/nar/gkv142

Vancouver

Tuplin A, Struthers M, Cook J, Bentley K, Evans DJ. Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail. Nucleic Acids Research. 2015 Mar 11;43(5):2914-2926. https://doi.org/10.1093/nar/gkv142

Author

Tuplin, Andrew ; Struthers, Madeleine ; Cook, Jonathan ; Bentley, Kirsten ; Evans, David J. / Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail. In: Nucleic Acids Research. 2015 ; Vol. 43, No. 5. pp. 2914-2926.

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@article{496a9bf6897a491ca08ce32ac7efba0d,
title = "Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail",
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.",
keywords = "Hepatitis-C-virus, Internal ribosome entry, CIS-acting replication, Dependent RNA-polymerase, 5 nontranslated region",
author = "Andrew Tuplin and Madeleine Struthers and Jonathan Cook and Kirsten Bentley and Evans, {David J.}",
note = "Date of Acceptance: 12/02/2015",
year = "2015",
month = "3",
day = "11",
doi = "10.1093/nar/gkv142",
language = "English",
volume = "43",
pages = "2914--2926",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "OXFORD UNIV PRESS",
number = "5",

}

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TY - JOUR

T1 - Inhibition of HCV translation by disrupting the structure and interactions of the viral CRE and 3' X-tail

AU - Tuplin, Andrew

AU - Struthers, Madeleine

AU - Cook, Jonathan

AU - Bentley, Kirsten

AU - Evans, David J.

N1 - Date of Acceptance: 12/02/2015

PY - 2015/3/11

Y1 - 2015/3/11

N2 - 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.

AB - 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.

KW - Hepatitis-C-virus

KW - Internal ribosome entry

KW - CIS-acting replication

KW - Dependent RNA-polymerase

KW - 5 nontranslated region

U2 - 10.1093/nar/gkv142

DO - 10.1093/nar/gkv142

M3 - Article

VL - 43

SP - 2914

EP - 2926

JO - Nucleic Acids Research

T2 - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 5

ER -

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