title: Modified dsRNAs that are not processed by Dicer maintain potency and are incorporated into the RISC.
abstract: Chemical modification of RNA duplexes can provide practical advantages for RNA interference (RNAi) triggering molecules including increased stability, safety and specificity. The impact of nucleotide modifications on Dicer processing, RISC loading and RNAi-mediated mRNA cleavage was investigated with duplexes >or=25 bp in length. It is known that dsRNAs >or=25 bp are processed by Dicer to create classic 19-bp siRNAs with 3'-end overhangs. We demonstrate that the presence of minimal modification configurations on longer RNA duplexes can block Dicer processing and result in the loading of the full-length guide strand into RISC with resultant mRNA cleavage at a defined site. These longer, modified duplexes can be highly potent gene silencers, with EC50s in the picomolar concentration range, demonstrating that Dicer processing is not required for incorporation into RISC or potent target silencing.
authors.affiliation: RXi Pharmaceuticals Corporation, Gateway Life Sciences Park, 60 Prescott Street, Worcester, MA 01605, USA.
authors.forename: William
authors.initials: W
authors.lastname: Salomon
authors.forename: Karen
authors.initials: K
authors.lastname: Bulock
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lapierre
authors.forename: Pamela
authors.initials: P
authors.lastname: Pavco
authors.forename: Tod
authors.initials: T
authors.lastname: Woolf
authors.forename: Joanne
authors.initials: J
authors.lastname: Kamens
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000737:chemistry* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism*; D058727:RNA, Small Untranslated
chemical_list: D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D034743:RNA-Induced Silencing Complex; D043244:Ribonuclease III; D058727:RNA, Small Untranslated