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Nucleic Acids Research 2005 33(15):4704-4710; doi:10.1093/nar/gki785
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Published online 19 August 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oupjournals.org

Article

Tolerated wobble mutations in siRNAs decrease specificity, but can enhance activity in vivo

Torgeir Holen1,2,*, Svein Erik Moe1, Jan Gunnar Sørbø1, Trine J. Meza2, Ole Petter Ottersen1 and Arne Klungland2,3

1Centre for Molecular Biology and Neuroscience (CMBN), and Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo Oslo, Norway 2Institute of Medical Microbiology, The National Hospital, University of Oslo 0027 Oslo, Norway 3Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo PO Box 1046, Blindern, N-0316 Oslo, Norway

*To whom correspondence should be addressed. Tel: +47 2285 1294; Fax: +47 2285 1488; Email: torgeir.holen{at}medisin.uio.no

Received June 24, 2005. Revised August 5, 2005. Accepted August 5, 2005.

RNA interference (RNAi) has become an invaluable tool for functional genomics. A critical use of this tool depends on an understanding of the factors that determine the specificity and activity of the active agent, small interfering RNA (siRNA). Several studies have concluded that tolerance of mutations can be considerable and hence lead to off-target effects. In this study, we have investigated in vivo the toleration of wobble (G:U) mutations in high activity siRNAs against Flap Endonuclease 1 (Fen1) and Aquaporin-4 (Aqp4). Mutations in the central part of the antisense strand caused a pronounced decrease in activity, while mutations in the 5' and 3'ends were tolerated very well. Furthermore, based on analysis of nine different mutated siRNAs with widely differing intrinsic activities, we conclude that siRNA activity can be significantly enhanced by wobble mutations (relative to mRNA), in the 5' terminal of the antisense strand. These findings should facilitate design of active siRNAs where the target mRNA offers limited choice of siRNA positions.


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