Leeder, W.-Matthias ; Reuss, Andreas J. ; Brecht, Michael ; Kratz, Katja ; Wachtveitl, Josef ; Göringer, H. Ulrich (2015)
Charge Reduction and Thermodynamic Stabilization of Substrate RNAs Inhibit RNA Editing.
In: PloS one, 10 (3)
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
African trypanosomes cause a parasitic disease known as sleeping sickness. Mitochondrial transcript maturation in these organisms requires a RNA editing reaction that is characterized by the insertion and deletion of U-nucleotides into otherwise non-functional mRNAs. Editing represents an ideal target for a parasite-specific therapeutic intervention since the reaction cycle is absent in the infected host. In addition, editing relies on a macromolecular protein complex, the editosome, that only exists in the parasite. Therefore, all attempts to search for editing interfering compounds have been focused on molecules that bind to proteins of the editing machinery. However, in analogy to other RNA-driven biochemical pathways it should be possible to stall the reaction by targeting its substrate RNAs. Here we demonstrate inhibition of editing by specific aminoglycosides. The molecules bind into the major groove of the gRNA/pre-mRNA editing substrates thereby causing a stabilization of the RNA molecules through charge compensation and an increase in stacking. The data shed light on mechanistic details of the editing process and identify critical parameters for the development of new trypanocidal compounds.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2015 |
| Autor(en): | Leeder, W.-Matthias ; Reuss, Andreas J. ; Brecht, Michael ; Kratz, Katja ; Wachtveitl, Josef ; Göringer, H. Ulrich |
| Art des Eintrags: | Bibliographie |
| Titel: | Charge Reduction and Thermodynamic Stabilization of Substrate RNAs Inhibit RNA Editing. |
| Sprache: | Englisch |
| Publikationsjahr: | 2015 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | PloS one |
| Jahrgang/Volume einer Zeitschrift: | 10 |
| (Heft-)Nummer: | 3 |
| Kurzbeschreibung (Abstract): | African trypanosomes cause a parasitic disease known as sleeping sickness. Mitochondrial transcript maturation in these organisms requires a RNA editing reaction that is characterized by the insertion and deletion of U-nucleotides into otherwise non-functional mRNAs. Editing represents an ideal target for a parasite-specific therapeutic intervention since the reaction cycle is absent in the infected host. In addition, editing relies on a macromolecular protein complex, the editosome, that only exists in the parasite. Therefore, all attempts to search for editing interfering compounds have been focused on molecules that bind to proteins of the editing machinery. However, in analogy to other RNA-driven biochemical pathways it should be possible to stall the reaction by targeting its substrate RNAs. Here we demonstrate inhibition of editing by specific aminoglycosides. The molecules bind into the major groove of the gRNA/pre-mRNA editing substrates thereby causing a stabilization of the RNA molecules through charge compensation and an increase in stacking. The data shed light on mechanistic details of the editing process and identify critical parameters for the development of new trypanocidal compounds. |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Genregulation und RNA-Therapeutika |
| Hinterlegungsdatum: | 10 Mär 2015 09:22 |
| Letzte Änderung: | 10 Mär 2015 09:22 |
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