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Cell Host Microbe. 2008 Jul 17;4(1):77-85. doi: 10.1016/j.chom.2008.05.013.

Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome.

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Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.


MicroRNAs usually interact with 3' noncoding regions (3'NCRs) of target mRNAs leading to downregulation of mRNA expression. In contrast, liver-specific microRNA miR-122 interacts with the 5' end of the hepatitis C virus RNA genome, resulting in increased viral RNA abundance. We find that inserting the viral miR-122 binding site into the 3' noncoding region of a reporter mRNA leads to downregulation of mRNA expression, indicating that the location of the miR-122 binding site dictates its effect on gene regulation. Furthermore, we discovered an adjacent, second miR-122 binding site, separated from the first by a highly conserved 14-nucleotide sequence. Mutational analysis demonstrates that both miR-122 binding sites in a single viral genome are occupied by the microRNA and function cooperatively to regulate target gene expression. These findings set a paradigm for dual, position-dependent functions of tandem microRNA-binding sites. Targeting an oligomeric microRNA complex offers potential as an antiviral-intervention strategy.

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