RNAi revised - Target mRNA-dependent enhancement of gene silencing

Dornseifer, Simon, Willkomm, Sarah, Far, Rosel Kretschmer Kazemi, Liebschwager, Janine, Beltsiou, Foteini, Frank, Kirsten, Laufer, Sandra D., Martinetz, Thomas, Sczakiel, Georg, Claussen, Jens Christian and Restle, Tobias (2015). RNAi revised - Target mRNA-dependent enhancement of gene silencing. Nucleic Acids Research, 43 (22), pp. 10623-10632.

Abstract

The discovery of RNA interference (RNAi) gave rise to the development of new nucleic acid-based technologies as powerful investigational tools and potential therapeutics. Mechanistic key details of RNAi in humans need to be deciphered yet, before such approaches take root in biomedicine and molecular therapy. We developed and validated an in silico-based model of siRNA-mediated RNAi in human cells in order to link in vitro-derived pre-steady state kinetic data with a quantitative and time-resolved understanding of RNAi on the cellular level. The observation that product release by Argonaute 2 is accelerated in the presence of an excess of target RNA in vitro inspired us to suggest an associative mechanism for the RNA slicer reaction where incoming target mRNAs actively promote dissociation of cleaved mRNA fragments. This novel associative model is compatible with highmultiple turnover rates of RNAibased gene silencing in living cells and accounts for target mRNA concentration-dependent enhancement of the RNAi machinery.

Publication DOI: https://doi.org/10.1093/nar/gkv1200
Divisions: Engineering & Applied Sciences
Additional Information: © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Uncontrolled Keywords: Genetics
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://academi ... 2/10623/1804139 (Publisher URL)
Published Date: 2015
Authors: Dornseifer, Simon
Willkomm, Sarah
Far, Rosel Kretschmer Kazemi
Liebschwager, Janine
Beltsiou, Foteini
Frank, Kirsten
Laufer, Sandra D.
Martinetz, Thomas
Sczakiel, Georg
Claussen, Jens Christian ( 0000-0002-9870-4924)
Restle, Tobias

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