The endoribonuclease Dicer heterogeneously cleaves short hairpin RNAs (shRNAs) into biologically active small interfering RNAs that have differing efficacies and off-target effects. This study found that promiscuous non-canonical cleavages by Dicer were prevented when the cleavage site was two nucleotides away from a bulge or loop structure. Hepatitis C virus-targeted shRNAs designed to include an internal loop two nucleotides away from the expected site of Dicer cleavage had reduced off-target effects. This finding could aid the design of shRNAs for inducing therapeutic RNA interference.
ORIGINAL RESEARCH PAPER
Gu, S. et al. The loop position of shRNAs and pre-miRNAs is critical for the accuracy of Dicer processing in vivo. Cell 151, 900–911 (2012)
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Harrison, C. Reducing off-target effects of shRNA. Nat Rev Drug Discov 12, 24 (2013). https://doi.org/10.1038/nrd3933
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DOI: https://doi.org/10.1038/nrd3933