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Differential hepatitis C virus RNA target site selection and host factor activities of naturally occurring miR-122 3΄ variants

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Abstract In addition to suppressing cellular gene expression, certain miRNAs potently facilitate replication of specific positive-strand RNA viruses. miR-122, a pro-viral hepatitis C virus (HCV) host factor, binds and recruits… Click to show full abstract

Abstract In addition to suppressing cellular gene expression, certain miRNAs potently facilitate replication of specific positive-strand RNA viruses. miR-122, a pro-viral hepatitis C virus (HCV) host factor, binds and recruits Ago2 to tandem sites (S1 and S2) near the 5΄ end of the HCV genome, stabilizing it and promoting its synthesis. HCV target site selection follows canonical miRNA rules, but how non-templated 3΄ miR-122 modifications impact this unconventional miRNA action is unknown. High-throughput sequencing revealed that a 22 nt miRNA with 3΄G (‘22–3΄G’) comprised <63% of total miR-122 in human liver, whereas other variants (23–3΄A, 23–3΄U, 21–3΄U) represented 11–17%. All loaded equivalently into Ago2, and when tested individually functioned comparably in suppressing gene expression. In contrast, 23–3΄A and 23–3΄U were more active than 22–3΄G in stabilizing HCV RNA and promoting its replication, whereas 21–3΄U was almost completely inactive. This lack of 21–3΄U HCV host factor activity correlated with reduced recruitment of Ago2 to the HCV S1 site. Additional experiments demonstrated strong preference for guanosine at nt 22 of miR-122. Our findings reveal the importance of non-templated 3΄ miR-122 modifications to its HCV host factor activity, and identify unexpected differences in miRNA requirements for host gene suppression versus RNA virus replication.

Keywords: rna; hcv; host factor; mir 122; virus

Journal Title: Nucleic Acids Research
Year Published: 2017

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