Dresden 2014 – wissenschaftliches Programm
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BP: Fachverband Biologische Physik
BP 15: Posters: Systems biology and neurosciences
BP 15.2: Poster
Dienstag, 1. April 2014, 09:30–12:30, P1
Reaction kinetics modeling of RNAi: gene silencing dependence of target mRNA concentration — •Simon Dornseifer1, Georg Sczakiel1, Tobias Restle1, and Jens Christian Claussen2 — 1IMM, Universität zu Lübeck, Germany — 2Computational Systems Biology Lab, Research II, Jacobs University Bremen, Germany
The discovery of post-transcriptional gene silencing via RNA interference (RNAi) gave rise to the development of new nucleic acid-based tools. Mechanistic key details of RNAi in human need to be deciphered yet. Here we propose and investigate a computational model of siRNA-mediated RNAi in human cells in order to link precise quantitative kinetic data and new molecular findings with a quantitative and time-resolved understanding of RNAi in the human system. Cell culture experiments suggest that the RNAi machinery adopts to large variations in target mRNA level, independent of siRNA or Ago2 concentrations. These experimental findings are not explained by the common literature view of RNAi, here termed dissociative mechanism, where the departing ligand (here, cleaved RNA fragments) leaves the complex in a slow step. Here, we investigate an alternatice, associative mechanism of target strand recognition by Argonaute 2 (Ago2). The associative model is compatible with the high multiple turnover rates of RNAi-based gene silencing in living cells and accounts for target mRNA concentration-dependent acceleration of the RNAi machinery. The associative model proposed here suggests that the efficacy of an siRNA or miRNA depends on the expression level of its target RNA such that high target levels allow better regulation via RNAi.