RNAi revised - Target mRNA-dependent enhancement of gene silencing

Simon Dornseifer, Sarah Willkomm, Rosel Kretschmer Kazemi Far, Janine Liebschwager, Foteini Beltsiou, Kirsten Frank, Sandra D. Laufer, Thomas Martinetz, Georg Sczakiel, Jens Christian Claussen, Tobias Restle*

*Corresponding author for this work
6 Citations (Scopus)


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.

Original languageEnglish
JournalNucleic Acids Research
Issue number22
Pages (from-to)10623-10632
Number of pages10
Publication statusPublished - 01.01.2015


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