Enhancement of hepatitis C viral RNA abundance by precursor miR-122 molecules |
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Authors: | Erica Machlin Cox Selena M. Sagan Stefanie A.W. Mortimer Jennifer A. Doudna Peter Sarnow |
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Affiliation: | 1.Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA;2.Department of Microbiology & Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada;3.Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA;4.Department of Chemistry, University of California, Berkeley, California 94720, USA;5.Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA |
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Abstract: | The hepatitis C viral RNA genome forms a complex with liver-specific microRNA (miR-122) at the extreme 5′ end of the viral RNA. This complex is essential to stabilize the viral RNA in infected cultured cells and in the liver of humans. The abundances of primary and precursor forms of miR-122, but not the abundance of mature miR-122, are regulated in a circadian rhythm in the liver of animals, suggesting a possible independent function of precursor molecules of miR-122 in regulating viral gene expression. Modified precursor molecules of miR-122 were synthesized that were refractory to cleavage by Dicer. These molecules were found to enhance the abundance of HCV RNA. Furthermore, they diminished the expression of mRNAs that contained binding sites for miR-122 in their 3′ noncoding regions. By use of duplex and precursor miR-122 mimetic molecules that carried mutations in the passenger strand of miR-122, the effects on viral and reporter gene expression could be pinpointed to the action of precursor miR-122 molecules. Targeting the circadian expression of precursor miR-122 by specific compounds likely provides novel therapeutic strategies. |
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Keywords: | hepatitis C virus microRNAs Dicer Argonaute 2 |
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