Specificity of microRNA target selection in translational repression.

By John G Doench, Phillip A. Sharp. Genes & Development, 2004

1,783 citations recorded by the source corpus.

MicroRNAs (miRNAs) are a class of noncoding RNAs found in organisms as evolutionarily distant as plants and mammals, yet most of the mRNAs they regulate are unknown. Here we show that the ability of an miRNA to translationally repress a target mRNA is largely dictated by the free energy of binding of the first eight nucleotides in the 5' region of the miRNA. However, G:U wobble base-pairing in this region interferes with activity beyond that predicted on the basis of thermodynamic stability. Furthermore, an mRNA can be simultaneously repressed by more than one miRNA species. The level of repression achieved is dependent on both the amount of mRNA and the amount of available miRNA complexes. Thus, predicted miRNA:mRNA interactions must be viewed in the context of other potential interactions and cellular conditions.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d0454855f99e5b7fe18aacba926ae47ff67c49e0

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Citations in the corpus

Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. (2006, background): “Most important for target recognition is pairing to the miRNA seed, defined as the 6 nt segment comprising nucleotides 2–7, counting from the 50 terminus of the miRNA (Lewis et al., 2003, 2005; Doench and Sharp, 2004; Brennecke et al., 2005).”
Passenger-strand cleavage facilitates assembly of siRNA into Ago2-containing RNAi enzyme complexes. (2005, neutral): “Passengerstrand cleavage appeared less important for this duplex than for the standard siRNA duplex (Figure 8B), a result consistent with computational and experimental studies of miRNA target specificity imply that single G:U wobble pairs in the seed disproportionately perturb small RNA binding (Le”
Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression (2007, background): “Although miRNAs may silence their targets via translational blocking (16), they also regulate target transcript levels.”
MicroRNAS and their regulatory roles in plants. (2006, background): “by some other means) can decrease protein output of mRNAs without corresponding decreases in message levels (34, 35, 110, 111).”
microRNA Target Predictions across Seven Drosophila Species and Comparison to Mammalian Targets (2005, background): “This idea is supported by experiments [17] and by results from computational approaches that have been used to search for target sites of different microRNAs in the same target mRNA [5,6,13].”
Argonaute proteins: key players in RNA silencing (2008, result): “This is in agreement with reports that imply that the extreme 5′-end nucleotide of siRNAs and miRNAs is not necessarily involved in recognition of the substrat”
A combined computational-experimental approach predicts human microRNA targets. (2004, background): “(10) Translational repression of miRNA targets bearing multiple MREs is largely determined by perfect complementarity between the MREs and the proximal miRNA region (Doench and Sharp 2004).”
Evolution of microRNA diversity and regulation in animals (2011, background): “Importantly, different target sites for different miRNAs within the same message act independently of each other, providing an additive effect of simultaneous repression by several miRNA”
Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. (2005, neutral): “The widespread impact of animal miRNAs on many target genes results from the flexibility of target-site recognition, where as little as a 7mer seed can confer regulation (Brennecke et al., 2005; Doench and Sharp, 2004 ).”
MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. (2011, background): “Multiple MREs on the same 3' UTR generally promote stronger silencing when situated at an optimal distance from each other (93, 94); although the mechanism for this is unknown, it has been speculated that multiple RISC complexes may stabilize each other through cooperative contacts (93).”
A three-dimensional view of the molecular machinery of RNA interference (2009, result): “This agrees well with numerous computational and biochemical studies indicating that nucleotides 2–8 of the guide strand (known as the 'seed' region) are crucial determinants of the specificity of target recognition by miRNA”
Tools for Sequence-Based miRNA Target Prediction: What to Choose? (2016, background): “In addition, it can act as a compensatory interaction when there is a mismatch in the seed [53,58,62,63].”
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