Drosophila miR2 Primarily Targets the m(7)GpppN Cap Structure for Translational Repression

作者：Zdanowicz Agnieszka; Thermann Rolf; Kowalska Joanna; Jemielity Jacek; Duncan Kent; Preiss Thomas; Darzynkiewicz Edward; Hentze Matthias W^*

来源：Molecular Cell, 2009, 35(6): 881-888.

DOI：10.1016/j.molcel.2009.09.009

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.

• 出版日期2009-9-24