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Nucleic Acids Research Advance Access originally published online on September 28, 2007
Nucleic Acids Research 2007 35(19):6598-6610; doi:10.1093/nar/gkm663
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Nucleic Acids Research, 2007, Vol. 35, No. 19 6598-6610
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Reduced levels of Ago2 expression result in increased siRNA competition in mammalian cells

Timothy A. Vickers*, Walt F. Lima, Josh G. Nichols and Stanley T. Crooke

Isis Pharmaceuticals. 1896 Rutherford Road, Carlsbad, CA 92008, USA

*To whom correspondence should be addressed. Tel: 760 931 9200; Fax: 760 268 4989; Email: tvickers{at}isisph.com

Received July 13, 2007. Revised August 9, 2007. Accepted August 10, 2007.

Administration of small interfering RNAs (siRNAs) leads to degradation of specific mRNAs utilizing the cellular RNA interference (RNAi) machinery. It has been demonstrated that co-administration of siRNAs may lead to attenuation of activity of one of the siRNAs. Utilizing antisense and siRNA-mediated RNA-induced silencing complex (RISC) gene reduction we show that siRNA competition is correlated with differences in the cellular expression levels of Ago2, while levels of other RISC proteins have no effect on competition. We also show that under certain conditions siRNA competition rather than reduction of cellular RISC levels may be responsible for apparent reduction in siRNA activity. Furthermore, exploiting siRNA competition, we show that the RISC pathway loads and results in detectable cleavage of the target RNA in ~2 h after transfection. The RISC pathway is also capable of being reloaded even in the absence of new protein synthesis. RISC reloading and subsequent induction of detectable cleavage of a new target RNA, requires about 9–12 h following the initial transfection.


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