Off-target effects by siRNA can induce toxic phenotype
Off-target effects by siRNA can induce toxic phenotype
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DOI：
10.1261/rna.28106
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发表时间：
2006-07-01
期刊：
影响因子：
4.5
通讯作者：
Khvorova, Anastasia
中科院分区：
文献类型：
--
作者：
Fedorov, Yuriy;Anderson, Emily M.;Khvorova, Anastasia
尽管最近的微阵列研究提供了RNA干扰（RNAi）介导的脱靶基因调节的证据，但对这些变化是否诱导可观察到的表型结果知之甚少。在这里，我们表明，一小部分随机选择的小抑制RNA（siRNA）可以诱导细胞活力的变化，在一个目标独立的方式。观察到的毒性需要完整的RNAi途径，并且可以通过添加减少脱靶效应的化学修饰来消除。此外，对毒性和无毒双链体的分析鉴定了毒性与毒性siRNA的RISC进入链中的4-碱基对基序（UGGC）的存在之间的强相关性。这篇文章提供了siRNA诱导的脱靶效应产生可测量表型的进一步证据，并提供了如何通过向siRNA添加化学修饰来减轻此类不良表型的示例。
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.