Kiran Kumar, Karthika Devi, Singh, Shubhangi, Schmelzle, Stella Maria, Vogel, Paul, Fruhner, Carolin, Hanswillemenke, Alfred, Brun, Adrian, Wettengel, Jacqueline, Füll, Yvonne, Funk, Lukas, Mast, Valentin, Botsch, J. Josephine, Reautschnig, Philipp, Li, Jin Billy, and Stafforst, Thorsten
RNA base editing relies on the introduction of adenosine-to-inosine changes into target RNAs in a highly programmable manner in order to repair disease-causing mutations. Here, we propose that RNA base editing could be broadly applied to perturb protein function by removal of regulatory phosphorylation and acetylation sites. We demonstrate the feasibility on more than 70 sites in various signaling proteins and identify key determinants for high editing efficiency and potent down-stream effects. For the JAK/STAT pathway, we demonstrate both, negative and positive regulation. To achieve high editing efficiency over a broad codon scope, we applied an improved version of the SNAP-ADAR tool. The transient nature of RNA base editing enables the comparably fast (hours to days), dose-dependent (thus partial) and reversible manipulation of regulatory sites, which is a key advantage over DNA (base) editing approaches. In summary, PTM interference might become a valuable field of application of RNA base editing. RNA base editing enables a precise, reversible and doseable change of genetic information. Here, authors propose base editing as a method to control post-translational modifications via removal of regulatory phosphorylation and acetylation sites, applying the approach to modulation of the JAK/STAT pathway via editing of wildtype alleles. [ABSTRACT FROM AUTHOR]