Target RNA-directed trimming and tailing of small silencing RNAs

By Stefan L Ameres, M. Horwich, Jui-Hung Hung, Jia Xu, Megha Ghildiyal, Zhiping Weng, Phillip D. Zamore. Science, 2010

621 citations recorded by the source corpus.

Close, But Not Too Close MicroRNAs (miRNAs) in plants are generally highly complementary to their target RNAs, yet, in most animal miRNAs, only the ∼8-nucleotide “seeds” sequence bases pair fully with the target, with few base pairs between the remainder of the miRNA and target. Plant miRNAs are methylated at their 3′ ends, whereas animals' miRNAs are not. Ameres et al. (p. 1534; see the Perspective by Pasquinelli) noticed that, in fruit flies, miRNAs engineered to have high complementarity to target RNAs were present at reduced levels. These miRNAs were trimmed and uridylated at their 3′ ends, features involved in RNA degradation. Fly small interfering RNAs, all of which are methylated at their 3′ ends, were unaffected, unless the methylating enzyme, Hen1, was mutated. Thus, 3′-methylation may prevent complementarity-driven remodeling and degradation of small RNAs. Animal microRNAs have reduced complementarity to their targets to avoid their own degradation. In Drosophila, microRNAs (miRNAs) typically guide Argonaute1 to repress messenger RNA (mRNA), whereas small interfering RNAs (siRNAs) guide Argonaute2 to destroy viral and transposon RNA. Unlike siRNAs, miRNAs rarely form extensive numbers of base pairs to the mRNAs they regulate. We find that extensive complementarity between a target RNA and an Argonaute1-bound miRNA triggers miRNA tailing and 3′-to-5′ trimming. In flies, Argonaute2-bound small RNAs—but not those bound to Argonaute1—bear a 2′-O-methyl group at their 3′ ends. This modification blocks target-directed small RNA remodeling: In flies lacking Hen1, the enzyme that adds the 2′-O-methyl group, Argonaute2-associated siRNAs are tailed and trimmed. Target complementarity also affects small RNA stability in human cells. These results provide an explanation for the partial complementarity between animal miRNAs and their targets.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6d9bdd18b33f2942f5ff1591a377482da13bcd82

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Citations in the corpus

MicroRNAs in stress signaling and human disease (2012, background): “Antagomirs associate with target miRNAs in the RISC, preventing their association with mRNA targets and promoting miRNA degradation (Ameres et al., 2010).”
Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018, background): “However, this interaction destabilizes the association between AGO and the 3 end of the miRNA promoting its degradation (48, 49).”
The long and short of microRNA. (2013, background): “For example, Ago-loaded RNAs are subjected to 30 tailing/trimming in a paralog-specific manner in both flies and humans but are also influenced by the target:miRNA complementarity—particularly at the miRNA 30 end (Ameres et al., 2010).”
Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp™ (2014, background): “Another difference between their experiments and ours is that their target contained bulged sites of a type that can induce miRNA degradation (Ameres et al., 2010), which might produce an apparent shift in the threshold.”
Optimization of enzymatic reaction conditions for generating representative pools of cDNA from small RNA (2010, background): “2005), and demonstrate that 39-end 29-O-methylation is functionally important for small RNA stability and function (Li et al. 2005; Horwich et al. 2007; Kurth and Mochizuki 2009; Ameres et al. 2010).”
Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. (2014, background): “Another difference between their experiments and ours is that their target contained bulged sites of a type that can induce miRNA degradation (Ameres et al., 2010), which might produce an apparent shift in the threshold.”
Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function (2017, background): “4, A to D); and (iii) the miR-7 binding site on Cyrano is unusual in that it has an extremely well conserved architecture that, similar to the miR-671 binding site on Cdr1as, could promote miR-7 removal by tailing and trimming (17, 36, 37).”
Metazoan MicroRNAs (2018, background): “The occurrence of TDMD among diverse eukaryotic species would explain why many classes of small silencing RNAs that routinely recognize targets with extensive complementarity (including piRNAs and endogenous siRNAs of animals, and miRNAs and siRNAs of plants) are methylated at their terminal 2′ oxyg”
microRNAs in action: biogenesis, function and regulation (2023, background): “Early studies indicated that engagement of miRNA with a highly complementary target can induce miRNA tailing or trimming 188,189 .”
MicroRNA Functions in Stress Responses (2010, positive): “Though the molecular mechanisms involved remain to be dissected, emerging data suggest that the specificity might lie at the 30 end of the miRNAs (Ameres et al., 2010; Cazalla et al., 2010), and several enzymes/cofactors have been implicated (Kai and Pasquinelli, 2010).”