Journal
MOLECULAR CELL
Volume 35, Issue 6, Pages 881-888Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2009.09.009
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Funding
- National Health and Medical Research Council of Australia
- Howard Hughes Medical Institute [55005604]
- National Science Support Project [PBZ-MNiSW-07/1/2007]
- Deutsche Forschungsgemeinschaft
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Understanding the molecular mechanism(s) of how miRNAs repress mRNA translation is a fundamental challenge in RNA biology. Here we use a validated cell-free system from Drosophila embryos to investigate how miR2 inhibits translation initiation. By screening a library of chemical m(7)GpppN cap structure analogs, we identified defined modifications of the triphosphate backbone that augment miRNA-mediated inhibition of translation initiation but are neutral toward general cap-dependent translation. Interestingly, these caps also augment inhibition by 4E-BP. Kinetic dissection of translational repression and miR2-induced deadenylation shows that both processes proceed largely independently, with establishment of the repressed state involving a slow step. Our data demonstrate a primary role for the m 7 GpppN cap structure in miRNA-mediated translational inhibition, implicate structural determinants outside the core eIF4E-binding region in this process, and suggest that miRNAs may target cap-dependent translation through a mechanism related to the 4E-BP class of translational regulators.
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