title: Off-target effects by siRNA can induce toxic phenotype.
abstract: Although recent microarray studies have provided evidence of RNA interference (RNAi)-mediated off-target gene modulation, little is known about whether these changes induce observable phenotypic outcomes. Here we show that a fraction of randomly selected small inhibitory RNAs (siRNAs) can induce changes in cell viability in a target-independent fashion. The observed toxicity requires an intact RNAi pathway and can be eliminated by the addition of chemical modifications that reduce off-target effects. Furthermore, an analysis of toxic and nontoxic duplexes identifies a strong correlation between the toxicity and the presence of a 4-base-pair motif (UGGC) in the RISC-entering strand of toxic siRNA. This article provides further evidence of siRNA-induced off-target effects generating a measurable phenotype and also provides an example of how such undesirable phenotypes can be mitigated by addition of chemical modifications to the siRNA.
authors: Dharmacon Research, Lafayette, CO 80026, USA. fedorov@dharmacon.com
authors: Yuriy
authors: Y
authors: Fedorov
authors: Emily M
authors: EM
authors: Anderson
authors: Amanda
authors: A
authors: Birmingham
authors: Angela
authors: A
authors: Reynolds
authors: Jon
authors: J
authors: Karpilow
authors: Kathryn
authors: K
authors: Robinson
authors: Devin
authors: D
authors: Leake
authors: William S
authors: WS
authors: Marshall
authors: Anastasia
authors: A
authors: Khvorova