Off-target effects by siRNA can induce toxic phenotype

被引：360

作者：

Fedorov, Yuriy ^{[1
]}

Anderson, Emily M. ^{[1
]}

Birmingham, Amanda ^{[1
]}

Reynolds, Angela ^{[1
]}

Karpilow, Jon ^{[1
]}

Robinson, Kathryn ^{[1
]}

Leake, Devin ^{[1
]}

Marshall, William S. ^{[1
]}

Khvorova, Anastasia ^{[1
]}

机构：

[1] Dharmacon Res, Lafayette, CO 80026 USA

来源：

RNA | 2006年 / 12卷 / 07期

关键词：

siRNA; off-target effects; RNAi; toxicity;

D O I：

10.1261/rna.28106

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

收藏

页码：1188 / 1196

页数：9

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