Dicer recognizes the 5′ end of RNA for efficient and accurate processing

By Jong-Eun Park, Inha Heo, Yuan Tian, D. Simanshu, Hyeshik Chang, David Jee, Dinshaw J. Patel, V. Narry Kim. 2011

526 citations recorded by the source corpus.

A hallmark of RNA silencing is a class of approximately 22-nucleotide RNAs that are processed from double-stranded RNA precursors by Dicer. Accurate processing by Dicer is crucial for the functionality of microRNAs (miRNAs). The current model posits that Dicer selects cleavage sites by measuring a set distance from the 3′ overhang of the double-stranded RNA terminus. Here we report that human Dicer anchors not only the 3′ end but also the 5′ end, with the cleavage site determined mainly by the distance (∼22 nucleotides) from the 5′ end (5′ counting rule). This cleavage requires a 5′-terminal phosphate group. Further, we identify a novel basic motif (5′ pocket) in human Dicer that recognizes the 5′-phosphorylated end. The 5′ counting rule and the 5′ anchoring residues are conserved in Drosophila Dicer-1, but not in Giardia Dicer. Mutations in the 5′ pocket reduce processing efficiency and alter cleavage sites in vitro. Consistently, miRNA biogenesis is perturbed in vivo when Dicer-null embryonic stem cells are replenished with the 5′-pocket mutant. Thus, 5′-end recognition by Dicer is important for precise and effective biogenesis of miRNAs. Insights from this study should also afford practical benefits to the design of small hairpin RNAs.

Subfields: Cancer Research, Molecular Biology

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Citations in the corpus

The RIG-I receptor adopts two different conformations for distinguishing host from viral RNA ligands (2022, background): “Avoiding p1dsRNAs is particularly critical given that microRNAs are frequently presented as uncapped, 50-monophosphorylated dsRNA molecules (Ghildiyal and Zamore, 2009; Park et al., 2011).”
The long and short of microRNA. (2013, background): “Human Dicer optimally processes pre-miRNAs with a 2 nt 30 overhang (Park et al., 2011).”
microRNAs in action: biogenesis, function and regulation (2023, background): “Subsequent work revealed a 5′-counting rule, whereby human Dicer can also recognize the 5′ phosphorylated end of the pre-miRNA hairpin and cleave the hairpin stem ~22 nucleotides from the 5′ end 52 .”
Metazoan MicroRNAs (2018, background): “In contrast to the other known noncanonical miRNAs, which require Dicer but not Drosha for their biogenesis (Figure 3B–”