miRNA-mediated gene silencing by translational repression followed by mRNA deadenylation and decay

By Sergej Djuranovic, Ali Nahvi, R. Green. Science, 2012

873 citations recorded by the source corpus.

Translation Block MicroRNAs (miRNAs) are small, noncoding RNA genes that are found in the genomes of most eukaryotes, where they play an important role in the regulation of gene expression. Although whether gene activity is repressed by blocking translation of messenger RNA (mRNA) targets, or by promoting their deadenylation and then degradation, has been open to debate. Bazzini et al. (p. 233, published online 15 March) and Djuranovic et al. (p. 237) looked at early points in the repression reaction in the zebrafish embryo or in Drosophila tissue culture cells, respectively, and found that translation was blocked before target mRNAs were significantly deadenylated and degraded. Thus, miRNAs appear to interfere with the initiation step of translation. MicroRNAs act to destroy their messenger RNA targets by blocking translation initiation, which leads to degradation. microRNAs (miRNAs) regulate gene expression through translational repression and/or messenger RNA (mRNA) deadenylation and decay. Because translation, deadenylation, and decay are closely linked processes, it is important to establish their ordering and thus to define the molecular mechanism of silencing. We have investigated the kinetics of these events in miRNA-mediated gene silencing by using a Drosophila S2 cell-based controllable expression system and show that mRNAs with both natural and engineered 3′ untranslated regions with miRNA target sites are first subject to translational inhibition, followed by effects on deadenylation and decay. We next used a natural translational elongation stall to show that miRNA-mediated silencing inhibits translation at an early step, potentially translation initiation.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/efdee0e2d938bf2d44634d7f46cd10fab47a77f2

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Citations in the corpus

Molecular mechanisms of RNA interference (2013, positive): “In the wake of cell-based studies implicating mRNA decay as the primary mode of silencing based on 12- and 32-h time points (30), two similar studies, each using multiple 2-h time points, demonstrated for the first time that translational repression precedes deadenylation and decay of a targeted miR”
Metazoan MicroRNAs (2018, background): “Examination of the dynamics of translational repression and mRNA destabilization as a miRNA is induced shows that although translational repression occurs rapidly (Bethune et al., 2012; Djuranovic et al., 2012), its effect on endogenous mRNAs is relatively weak, such that by the time consequential r”
Biogenesis, Turnover, and Mode of Action of Plant MicroRNAs[OPEN] (2013, background): “In animals, kinetic analysis has demonstrated that translational repression precedes mRNA deadenylation and destabilization (Fabian et al., 2009; Bazzini et al., 2012; Béthune et al., 2012; Djuranovic et al., 2012) and may be required for mRNA destabilization (Meijer et al., 2013).”
The Functions of MicroRNAs: mRNA Decay and Translational Repression. (2015, methodology): “Kinetic studies using reporter mRNAs were performed in Drosophila S2 cells and HeLa cells, and confirmed that translational repression occurs before deadenylation andmRNA decay [63,132].”