Journal
ACS CHEMICAL BIOLOGY
Volume 6, Issue 1, Pages 47-60Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb100358f
Keywords
microRNA (miRNA); RISC; RNA Interference; RNAI off-target effect; Short interfering RNA (siRNA); siRNA multiplicity validation; siRNA or miRNA seed sequence
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Funding
- Sanofi-Aventis
- Lynch Foundation
- National Institutes of Health (Dana Farber-Harvard Cancer Center Breast Cancer SPORE) [GM66492, CA89393]
- NATIONAL CANCER INSTITUTE [P50CA089393] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R56GM066492, R01GM066492] Funding Source: NIH RePORTER
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In the 12 years since the process of RNA interference (RNAi) was first discovered, great progress has been made in understanding its mechanism and exploiting its ability to silence gene expression to study gene function at a genome-wide level. Its extensive use as a screening method has yielded many published lists of genes that play novel roles in higher eukaryotes. However, the usefulness of this information is potentially limited by the occurrence of unintended off-target effects. Here we review the potential causes of off-target effects and the Impact of this phenomenon in interpreting the results of high-throughput RNAI screens. In addition to targeting the intended gene product, artificial short interfering RNAs (siRNAs) can produce off-target effects by down-regulating the expression of multiple mRNAs through microRNA-like targeting of the 3' untranslated region. We examine why this phenomenon can produce high hit rates in siRNA screens and why independent validation of screening results is critical for the approach to yield new biological insights.
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