RNAi revised - Target mRNA-dependent enhancement of gene silencing

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: College of Engineering & Physical 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
Publication ISSN: 1362-4962
Last Modified: 10 May 2024 07:12
Date Deposited: 09 Nov 2018 15:12
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
https://academi ... 2/10623/1804139 (Publisher URL)
PURE Output Type: Article
Published Date: 2015-12-15
Published Online Date: 2015-11-17
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 (ORCID Profile 0000-0002-9870-4924)
Restle, Tobias

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