Translational Repression and eIF4A2 Activity Are Critical for MicroRNA-Mediated Gene Regulation

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Science  05 Apr 2013:
Vol. 340, Issue 6128, pp. 82-85
DOI: 10.1126/science.1231197

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MicroRNA Mechanism

MicroRNAs are small noncoding RNAs that regulate gene expression by binding complementary target messenger RNAs (mRNAs) and repressing their expression through repression of protein translation and mRNA degradation. Meijer et al. (p. 82) show that in a HeLa cell system mRNA degradation is a consequence of translational inhibition via the initiation factor eIF4A2.


MicroRNAs (miRNAs) control gene expression through both translational repression and degradation of target messenger RNAs (mRNAs). However, the interplay between these processes and the precise molecular mechanisms involved remain unclear. Here, we show that translational inhibition is the primary event required for mRNA degradation. Translational inhibition depends on miRNAs impairing the function of the eIF4F initiation complex. We define the RNA helicase eIF4A2 as the key factor of eIF4F through which miRNAs function. We uncover a correlation between the presence of miRNA target sites in the 3′ untranslated region (3′UTR) of mRNAs and secondary structure in the 5′UTR and show that mRNAs with unstructured 5′UTRs are refractory to miRNA repression. These data support a linear model for miRNA-mediated gene regulation in which translational repression via eIF4A2 is required first, followed by mRNA destabilization.

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