Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast

In order to clarify the biological relevance of gene translational errors we have engineered codon misreading in yeast and used profiling of total and polysome-associated mRNAs, molecular and biochemical tools to characterize the recombinant cells. We demonstrate here that gene translational errors, which have negligible impact on yeast growth rate down-regulate protein synthesis, activate the unfolded protein response and environmental stress response pathways, and down-regulate chaperones linked to ribosomes.We provide the first global view of transcriptional and post-transcriptional responses to global gene translational errors and we postulate that they cause gradual cell degeneration through synergistic effects of overloading protein quality control systems and deregulation of protein synthesis, but generate adaptive phenotypes in unicellular organisms through activation of stress cross-protection. We conclude that these genome wide gene translational infidelities can be degenerative or adaptive depending on cellular context and physiological condition.Genome decoding fidelity is essential to maintain cell homeostasis and fitness in all organisms. However, errors in DNA transcription, pre-mRNA splicing and editing, and in mRNA translation, generate mutant proteins whose toxicity creates homeostatic imbalances (proteotoxic stress). At the gene translation level, missense, nonsense, frameshifting and ribosome drop-off errors affect protein synthesis [1]. Missense errors arise from incorrect tRNA selection by the ribosome or incorrect tRNA aminoacylation by aminoacyl-tRNA synthetases (aaRSs) and occur with average frequency of 10-3 to 10-5 per codon decoded [2-4]. Such errors are codon-dependent and are sensitive to the nutritional status of the cell [5,6]. Translational frameshifting errors occur at a frequency of 10-5 and are caused by tRNA slippage during mRNA decoding [1], while read-through of stop codons (nonsense errors) results from competition between non