Regensburg 2016 – wissenschaftliches Programm
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BP: Fachverband Biologische Physik
BP 59: DNA, RNA and Related Enzymes
BP 59.4: Vortrag
Donnerstag, 10. März 2016, 10:30–10:45, H45
RNAi revised - target mRNA-dependent enhancement of gene silencing — •Simon Dornseifer1, Sarah Willkomm1, Rosel Kretschmer-Kazemi Far1, Janine Libschwager1, Foteini Beltsiou1, Kirsten Frank1, Sandra D. Laufer1, Thomas Martinetz2, Georg Sczakiel1, Jens Christian Claussen3,2, and Tobias Restle1 — 1Inst. Molecular Medicine, Univ. Lübeck — 2INB, Univ. Lübeck — 3Comp. Systems Biol., Jacobs Univ. Bremen
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 [1] 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 high multiple turnover rates of RNAi-based gene silencing in living cells and accounts for target mRNA concentration-dependent enhancement of the RNAi machinery [1].
[1] S. Dornseifer et al, Nucleic Acids Research (Epub ahead of print 2015) http://dx.doi.org/10.1093/nar/gkv1200