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

Jong-Eun Park, Inha Heo, Yuan Tian, Dhirendra K. Simanshu, Hyeshik Chang, David Jee, Dinshaw J. Patel and V. Narry Kim ()
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Jong-Eun Park: School of Biological Sciences, Seoul National University
Inha Heo: School of Biological Sciences, Seoul National University
Yuan Tian: Structural Biology Program, Memorial-Sloan Kettering Cancer Center
Dhirendra K. Simanshu: Structural Biology Program, Memorial-Sloan Kettering Cancer Center
Hyeshik Chang: School of Biological Sciences, Seoul National University
David Jee: School of Biological Sciences, Seoul National University
Dinshaw J. Patel: Structural Biology Program, Memorial-Sloan Kettering Cancer Center
V. Narry Kim: School of Biological Sciences, Seoul National University

Nature, 2011, vol. 475, issue 7355, 201-205

Abstract: Abstract 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.

Date: 2011
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DOI: 10.1038/nature10198

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