Nucleic Acids Research Advance Access originally published online on August 28, 2007
Nucleic Acids Research 2007 35(17):5886-5897; doi:10.1093/nar/gkm548
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Nucleic Acids Research, 2007, Vol. 35, No. 17 5886-5897
© 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.
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Improved silencing properties using small internally segmented interfering RNAs
1Department of Molecular Biology, University of Aarhus, DK-8000, Aarhus C, 2Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, DK-5230 Odense, and 3RiboTask ApS, Sdr. Boulevard 44-3, DK-5000 Odense C, Denmark
*To whom correspondence should be addressed. Tel: +45 8942 2686; Fax: +45 8619 6500; Email: jk{at}mb.au.dk
Received February 28, 2007. Revised July 5, 2007. Accepted July 5, 2007.
RNA interference is mediated by small interfering RNAs (siRNAs) that upon incorporation into the RNA-induced silencing complex (RISC) can target complementary mRNA for degradation. Standard siRNA design usually feature a 19–27 base pair contiguous double-stranded region that is believed to be important for RISC incorporation. Here, we describe a novel siRNA design composed of an intact antisense strand complemented with two shorter 10–12 nt sense strands. This three-stranded construct, termed small internally segmented interfering RNA (sisiRNA), is highly functional demonstrating that an intact sense strand is not a prerequisite for RNA interference. Moreover, when using the sisiRNA design only the antisense strand is functional in activated RISC thereby completely eliminating unintended mRNA targeting by the sense strand. Interestingly, the sisiRNA design supports the function of chemically modified antisense strands, which are non-functional within the context of standard siRNA designs. This suggests that the sisiRNA design has a clear potential of improving the pharmacokinetic properties of siRNA in vivo.
Present address: Jørgen Kjems, Department of Molecular Biology, University of Aarhus, C. F. Møllers Allé 1130, DK-8000 Århus C, Denmark. Christian K Damgaard, Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, CO, USA.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.