Weak Seed-Pairing Stability and High Target-Site Abundance Decrease the Proficiency of lsy-6 and Other miRNAs

By David M. Garcia, Daehyun Baek, Chanseok Shin, George W. Bell, Andrew Grimson, David P. Bartel. Nature Structural &Molecular Biology, 2011

898 citations recorded by the source corpus.

Most metazoan microRNAs (miRNAs) target many genes for repression, but the nematode lsy-6 miRNA is much less proficient. Here we show that the low proficiency of lsy-6 can be recapitulated in HeLa cells and that miR-23, a mammalian miRNA, also has low proficiency in these cells. Reporter results and array data indicate two properties of these miRNAs that impart low proficiency: their weak predicted seed-pairing stability (SPS) and their high target-site abundance (TA). These two properties also explain differential propensities of small interfering RNAs (siRNAs) to repress unintended targets. Using these insights, we expand the TargetScan tool for quantitatively predicting miRNA regulation (and siRNA off-targeting) to model differential miRNA (and siRNA) proficiencies, thereby improving prediction performance. We propose that siRNAs designed to have both weaker SPS and higher TA will have fewer off-targets without compromised on-target activity.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/f90bc602434d53832b9523362b011e270796a890

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Citations in the corpus

The biochemical basis of microRNA targeting efficacy (2018, background): “Thus, although lsy-6, which has unusually poor predicted seed-pairing stability (29), did indeed have theweakest site-binding affinity of the sixmiRNAs, the difference between its binding affinity and that of the other miRNAs was less than might have been expected.”
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Mapping the Human miRNA Interactome by CLASH Reveals Frequent Noncanonical Binding (2013, neutral): “…Inc. pairs with the target; (2) nucleotides paired outside the seed region stabilize interactions but are reported not to influence miRNA efficacy (Garcia et al., 2011; Grimson et al., 2007); and (3) functional miRNA targets are localized close to the extremes of the 30 UTRs of…”
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