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 mediated by the RNA editing by the adenosine deaminase acting on RNA (ADAR) enzyme, in which genomically encoded adenosines are transformed and recognized as guanosines in the RNA sequence, is an endogenous and powerful means of creating inner transcriptome diversity. When editing occurs within mRNAs, it can recode specific codons, leading to changes in protein structure and function. In mammals, these editing events are usually located within the noncoding Alu-elements. However, cephalopods are an intriguing exception: the majority of their mRNAs harbor recording events, and this creates enormous protein diversity. Because cephalopods are behaviorally complex, these findings raise the possibility that massive transcriptome diversification enables phenotypic diversity and flexibility. An interesting prediction is that as a cost, similarly to DNA mutations, it can also serve as a source for proteotoxic stress. To test this possibility, we exogenously expressed ADAR proteins in our model system, the yeast Saccharomyces-cerevisiae, an organism whose origins precede the emergence of ADAR, but can express 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 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.