Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 10, Pages 5307-5324Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkz194
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Funding
- McGill University
- NSERC Discovery grant program [RGPIN-2014-05907]
- US National Institutes of Health [R01-GM104475, R01-GM115649, R35-GM127090]
- Swiss National Science Foundation [Advanced Postdoc Mobility Fellowship] [P300PA_177860]
- NYU Abu Dhabi
- Canada Research Chairs program
- NSERC
- Swiss National Science Foundation (SNF) [P300PA_177860] Funding Source: Swiss National Science Foundation (SNF)
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Hepatitis C virus (HCV) is a positive-sense RNA virus that interacts with the liver-specific microRNA, miR-122. miR-122 binds to two sites in the 5 untranslated region (UTR) and this interaction promotes HCV RNA accumulation, although the precise role of miR-122 in the HCV life cycle remains unclear. Using biophysical analyses and Selective 2 Hydroxyl Acylation analyzed by Primer Extension (SHAPE) we investigated miR-122 interactions with the 5 UTR. Our data suggests that miR-122 binding results in alteration of nucleotides 1-117 to suppress an alternative secondary structure and promote functional internal ribosomal entry site (IRES) formation. Furthermore, we demonstrate that two hAgo2:miR-122 complexes are able to bind to the HCV 5 terminus simultaneously and SHAPE analyses revealed further alterations to the structure of the 5 UTR to accommodate these complexes. Finally, we present a computational model of the hAgo2:miR-122:HCV RNA complex at the 5 terminus of the viral genome as well as hAgo2:miR-122 interactions with the IRES-40S complex that suggest hAgo2 is likely to form additional interactions with SLII which may further stabilize the HCV IRES. Taken together, our results support a model whereby hAgo2:miR-122 complexes alter the structure of the viral 5 terminus and promote formation of the HCV IRES.
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