(original) (raw)

TY - JOUR AU - Marques, Joao Trindade AU - Devosse, Thalie AU - Wang, Die AU - Zamanian-Daryoush, Maryam AU - Serbinowski, Paul AU - Hartmann, Rune AU - Fujita, Takashi AU - Behlke, Mark A AU - Williams, Bryan RG PY - 2006 DA - 2006/05/01 TI - A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells JO - Nature Biotechnology SP - 559 EP - 565 VL - 24 IS - 5 AB - 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. SN - 1546-1696 UR - https://doi.org/10.1038/nbt1205 DO - 10.1038/nbt1205 ID - Marques2006 ER -