HAU16008-04-4 - insight review articles RNA interference...

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insight review articles 244 NATURE | VOL 418 | 11 JULY 2002 | www.nature.com/nature T he phenomenon of RNAi was first discovered in the nematode worm Caenorhabditis elegans as a response to double-stranded RNA (dsRNA), which resulted in sequence-specific gene silencing 1 . Following on from the studies of Guo and Kemphues, who had found that sense RNA was as effective as antisense RNA for suppressing gene expression in worms 2 , Fire, Mello and colleagues 1 were attempting to use antisense RNA as an approach to inhibit gene expression. Their breakthrough was to test the synergy of sense and antisense RNAs, and they duly found that the dsRNA mixture was at least tenfold more potent as a silencing trigger than were sense or antisense RNAs alone 1 . Silencing by dsRNAs had a number of remarkable properties — RNAi could be provoked by injection of dsRNA into the C. elegans gonad or by introduction of dsRNA through feeding either of dsRNA itself or of bacteria engineered to express it 3 . Furthermore, exposure of a parental animal to only a few molecules of dsRNA per cell triggered gene silencing throughout the treated animal (systemic silencing) and in its F 1 (first generation) progeny (Fig. 1). From this discovery emerged the notion that a number of previously characterized, homology-dependent gene- silencing mechanisms might share a common biological root. Several years previously, Richard Jorgensen had been engineering transgenic petunias with the goal of altering pigmentation. But introducing exogenous transgenes did not deepen flower colour as expected. Instead, flowers showed variegated pigmentation, with some lacking pigment altogether (refs 4, 5, and reviewed in ref. 6). This indicated that not only were the transgenes themselves inactive, but also that the added DNA sequences somehow affected expression of the endogenous loci. This phenome- non, called co-suppression, can be produced by highly expressed, single-copy transgenes 7,8 or by transgenes, expressed at a more modest level, that integrate into the genome in complex, multicopy arrays 9 . In parallel, several laboratories found that plants responded to RNA viruses by targeting viral RNAs for destruction 10–13 . Notably, silencing of endogenous genes could also be triggered by inclusion of homologous sequences in a virus replicon. What is clear in retrospect is that both complex trans- gene arrays and replicating RNA viruses generate dsRNA. In plant systems, dsRNAs that are introduced from exogenous sources or that are transcribed from engineered inverted repeats are potent inducers of gene silencing (reviewed in ref. 14). But co-suppression phenomena are not restricted to plants: similar outcomes have been noted in unicellular organisms, such as Neurospora , and in metazoans, such as Drosophila , C. elegans and mammals 15–18 . In a few cases, silencing has been correlated with integration of transgenes as complex arrays that can produce dsRNA directly, although silencing can also be triggered by the presence of
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HAU16008-04-4 - insight review articles RNA interference...

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