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Nucleic Acids Research, 2000, Vol. 28, No. 2 582-592
© 2000 Oxford University Press

Nucleocytoplasmic shuttling: a novel in vivo property of antisense phosphorothioate oligodeoxynucleotides

Peter Lorenz, Tom Misteli, Brenda F. Baker1, C. Frank Bennett1 and David L. Spector*

Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA and 1ISIS Pharmaceuticals, Carlsbad, CA 92008, USA

Phosphorothioate oligodeoxynucleotides (P=S ODNs) are frequently used as antisense agents to specifically interfere with the expression of cellular target genes. However, the cell biological properties of P=S ODNs are poorly understood. Here we show that P=S ODNs were able to continuously shuttle between the nucleus and the cytoplasm and that shuttling P=S ODNs retained their ability to act as antisense agents. The shuttling process shares characteristics with active transport since it was inhibited by chilling and ATP depletion in vivo. Transport was carrier-mediated as it was saturable, and nuclear pore complex-mediated as it was sensitive to treatment with wheatgerm agglutinin. Oligonucleotides without a P=S backbone chemistry were only weakly restricted in their migration by chilling, ATP depletion and wheatgerm agglutinin and thus moved by diffusion. P=S ODN shuttling was only moderately affected by disruption of the Ran/RCC1 system. We propose that P=S ODNs shuttle through their binding to yet unidentified cellular molecules that undergo nucleocytoplasmic transport via a pathway that is not as strongly dependent on the Ran/RCC1 system as nuclear export signal-mediated protein export, U-snRNA, tRNA and mRNA export. The shuttling property of P=S ODNs must be taken into account when considering the mode and site of action of these antisense agents.

* To whom correspondence should be addressed. Tel: +1 516 367 8456; Fax: +1 516 367 8876; Email: spector@cshl.org Present addresses: Peter Lorenz, Institute of Immunology, University of Rostock, Schillingallee 70, D-18055 Rostock, Germany Tom Misteli, National Cancer Institute/NIH, 41 Library Drive, Bethesda, MD 20892, USA


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