Chemistry & Biology
Volume 11, Issue 8, August 2004, Pages 1165-1175
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Article
Visualizing a Correlation between siRNA Localization, Cellular Uptake, and RNAi in Living Cells

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Abstract

RNA interference (RNAi) is the process by which short-interfering RNA (siRNA) target a specific mRNA for degradation through interactions with an RNA-induced silencing complex (RISC). Here, a clear correlation between siRNA localization, cellular uptake, and RNAi activity was discovered by delivering siRNA into cells using siRNA-TAT47-57 peptide, siRNA-TAT47-57-derived oligocarbamate conjugates, or nanoparticles. For successful RNAi, the localization of siRNA was distinctly perinuclear, suggesting that siRNA is targeted to these regions for interactions with RISC to induce RNAi. siRNA sequence variation and the presence of the target mRNA apparently did not change the subcellular localization pattern of siRNA. Intriguingly, siRNA conjugated to TAT47-57 peptide or TAT47-57-derived oligocarbamate resulted in efficient RNAi activity and perinuclear localization of siRNA that was distinctly different from nonconjugated free TAT peptide nucleolar localization. These results suggest that interactions with RISC dictate siRNA localization even when siRNA is conjugated to TAT47-57 peptide.

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Present address: Gladstone Institute of Virology and Immunology, University of California, San Francisco, 365 Vermont Street, San Francisco, California 94103.