Nature Biotechnology 24, 559 - 565 (2006)
Published online: 30 April 2006; | doi:10.1038/nbt1205
A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cellsJoao Trindade Marques1, Thalie Devosse1, Die Wang1, Maryam Zamanian-Daryoush1, Paul Serbinowski1, Rune Hartmann2, Takashi Fujita3, Mark A Behlke4
& Bryan RG Williams1, 51
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. 2
Department of Molecular Biology, University of Aarhus, DK-8000 Aarhus, Denmark. 3
Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan. 4
Integrated DNA Technologies, Inc., Coralville, Iowa 52241, USA. 5
Monash Institute of Medical Research, Monash University, 246 Clayton Road, Clayton, VIC. 3168, Melbourne, Australia.
Correspondence should be addressed to Bryan RG Williams bryan.williams@med.monash.edu.au Nonspecific effects triggered by small interfering RNAs (siRNAs) complicate the use of RNA interference (RNAi) to specifically downregulate gene expression1,
2,
3,
4,
5. To uncover the basis of these nonspecific activities, we analyzed the effect of chemically synthesized siRNAs on mammalian double-stranded RNA (dsRNA)-activated signaling pathways. siRNAs ranging from 21 to 27 nucleotides (nt) in length activated the interferon system when they lacked 2-nt 3' overhangs, a characteristic of Dicer products. We show that the recognition of siRNAs is mediated by the RNA helicase RIG-I and that the presence of 3' overhangs impairs its ability to unwind the dsRNA substrate and activate downstream signaling to the transcription factor IRF-3. These results suggest a structural basis for discrimination between microRNAs that are endogenous Dicer products, and nonself dsRNAs such as by-products of viral replication. These findings will enable the rational design of siRNAs that avoid nonspecific effects or, alternatively, that induce bystander effects to potentially increase the efficacy of siRNA-based treatments of viral infections or cancer.
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