Nucleic Acids Research Advance Access originally published online on February 10, 2009
Nucleic Acids Research 2009 37(6):1925-1935; doi:10.1093/nar/gkp048
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Nucleic Acids Research, 2009, Vol. 37, No. 6 1925-1935
© 2009 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.
Chemistry and Synthetic Biology |
A synthetic snRNA m3G-CAP enhances nuclear delivery of exogenous proteins and nucleic acids
1Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Huddinge, 2Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 57 Huddinge and 3Department of Cell and Molecular Biology, The Medical Nobel Institutet, Box 285, Karolinska Institutet, Stockholm SE-171 77, Sweden
*To whom correspondence should be addressed. Tel: +0046858583663; Fax: +0046858583650; Email: pedro.moreno{at}ki.se Correspondence may also be addressed to C. I. Edvard Smith. Tel: +0046858583651; Fax: +0046858583650; Email: edvard.smith{at}ki.se
Received January 7, 2009. Revised January 16, 2009. Accepted January 16, 2009.
Accessing the nucleus through the surrounding membrane poses one of the major obstacles for therapeutic molecules large enough to be excluded due to nuclear pore size limits. In some therapeutic applications the large size of some nucleic acids, like plasmid DNA, hampers their access to the nuclear compartment. However, also for small oligonucleotides, achieving higher nuclear concentrations could be of great benefit. We report on the synthesis and possible applications of a natural RNA 5'-end nuclear localization signal composed of a 2,2,7-trimethylguanosine cap (m3G-CAP). The cap is found in the small nuclear RNAs that are constitutive part of the small nuclear ribonucleoprotein complexes involved in nuclear splicing. We demonstrate the use of the m3G signal as an adaptor that can be attached to different oligonucleotides, thereby conferring nuclear targeting capabilities with capacity to transport large-size cargo molecules. The synthetic capping of oligos interfering with splicing may have immediate clinical applications.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.