RNA editing by dysregulated Adenosine Deaminase Acting on RNA (ADAR) enzyme induces proteotoxic stress

Traditionally, DNA mutations are considered to bear the sole responsibility for alterations in genomic information. However, A-to-I RNA editing, in which genomically encoded adenosines are transformed and recognized as guanosines in the RNA sequence, is an endogenous and powerful mean of creating inner transcriptome diversity. The magnitude of A-to-I RNA editing is unprecedented, with millions of sites already identified in the human genome. The vast majority of these editing events in human are usually located within the noncoding Alu elements. An interesting predication is that similarly to DNA mutations, RNA editing can also serve as a source for proteotoxic stress. To test this possibility, we exogenously expressed ADAR proteins in our favorite model system, the yeast Saccharomyces cerevisiae, an organism whose origins precede the emergence of ADAR, but can expresses ADARs originated from different organisms. The results showed that such expression caused massive RNA editing, which significantly reduced cell fitness. Furthermore, mass-spectrometry analysis revealed that many of the RNA editing events resulted in increased protein diversity, which enhanced their ubiquitination and tendency to aggregate. Hence, our results suggest that the A-to-I RNA editing events induced by ADAR dysregulation are manifested at the proteomic levels, and are an overlooked source of proteotoxic stress. We are currently in the process of testing our hypothesis in mammalian cells expressing a dysregulated version of the ADAR proteins.