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RNAi revised - target mRNA-dependent enhancement of gene silencing
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 molecula...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678823/ https://www.ncbi.nlm.nih.gov/pubmed/26578554 http://dx.doi.org/10.1093/nar/gkv1200 |
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author | Dornseifer, Simon Willkomm, Sarah Far, Rosel Kretschmer-Kazemi Liebschwager, Janine Beltsiou, Foteini Frank, Kirsten Laufer, Sandra D. Martinetz, Thomas Sczakiel, Georg Claussen, Jens Christian Restle, Tobias |
author_facet | Dornseifer, Simon Willkomm, Sarah Far, Rosel Kretschmer-Kazemi Liebschwager, Janine Beltsiou, Foteini Frank, Kirsten Laufer, Sandra D. Martinetz, Thomas Sczakiel, Georg Claussen, Jens Christian Restle, Tobias |
author_sort | Dornseifer, Simon |
collection | PubMed |
description | 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 high multiple turnover rates of RNAi-based gene silencing in living cells and accounts for target mRNA concentration-dependent enhancement of the RNAi machinery. |
format | Online Article Text |
id | pubmed-4678823 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-46788232015-12-16 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 Restle, Tobias Nucleic Acids Res Computational Biology 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 high multiple turnover rates of RNAi-based gene silencing in living cells and accounts for target mRNA concentration-dependent enhancement of the RNAi machinery. Oxford University Press 2015-12-15 2015-11-17 /pmc/articles/PMC4678823/ /pubmed/26578554 http://dx.doi.org/10.1093/nar/gkv1200 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ 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 |
spellingShingle | Computational Biology Dornseifer, Simon Willkomm, Sarah Far, Rosel Kretschmer-Kazemi Liebschwager, Janine Beltsiou, Foteini Frank, Kirsten Laufer, Sandra D. Martinetz, Thomas Sczakiel, Georg Claussen, Jens Christian Restle, Tobias RNAi revised - target mRNA-dependent enhancement of gene silencing |
title | RNAi revised - target mRNA-dependent enhancement of gene silencing |
title_full | RNAi revised - target mRNA-dependent enhancement of gene silencing |
title_fullStr | RNAi revised - target mRNA-dependent enhancement of gene silencing |
title_full_unstemmed | RNAi revised - target mRNA-dependent enhancement of gene silencing |
title_short | RNAi revised - target mRNA-dependent enhancement of gene silencing |
title_sort | rnai revised - target mrna-dependent enhancement of gene silencing |
topic | Computational Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678823/ https://www.ncbi.nlm.nih.gov/pubmed/26578554 http://dx.doi.org/10.1093/nar/gkv1200 |
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