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Free energy lights the path toward more effective RNAi

Nature Genetics volume 35, pages 303–305 (2003)Cite this article

Silencing gene expression by RNA interference (RNAi) has become a daily activity for mammalian cell biologists. Those who often use this approach have come to appreciate its occasional frustrations and potential limitations. A pair of recent papers in Cell provides rules for designing short interfering RNAs (siRNAs) that are both validated at the practical level and understood mechanistically.

The discovery that double-stranded RNA can elicit RNAi, a specific, potent gene silencing response, began a genetic revolution in those organisms for which genetic approaches were largely unavailable or inconvenient. Generally, the interference process initiates with the processing of a double-stranded RNA by Dicer (reviewed in ref. 1). This RNaseIII-class enzyme creates siRNAs, which comprise duplexes of ∼19 nucleotides (nt) bounded by 2-nt 3′ overhangs. The siRNAs become incorporated into the RNA-induced silencing complex (RISC), which uses such sequences as guides to the selection of its substrates by Watson-Crick base-pairing interactions. Thus, siRNAs must be unwound for exposure to potential targets, which is thought to be mediated by an ATP-dependent RNA helicase2. Single-stranded versions of siRNAs can be used to trigger RISC assembly in vitro in both Drosophila melanogaster and mammalian cell extracts, although they are less efficient triggers than double-stranded siRNAs3,4.

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Figure 1: Doing it the natural way.
Figure 2: Habits of highly effective siRNAs.

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  1. Cold Spring Harbor Laboratory, Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, 11724, New York, USA

    Jose M Silva, Ravi Sachidanandam & Gregory J Hannon

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  1. Jose M Silva
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  2. Ravi Sachidanandam
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  3. Gregory J Hannon
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Silva, J., Sachidanandam, R. & Hannon, G. Free energy lights the path toward more effective RNAi. Nat Genet 35, 303–305 (2003). https://doi.org/10.1038/ng1203-303

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