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

Abstract

BackgroundOrganisms use highly accurate molecular processes to transcribe their genes and a variety of mRNA quality control and ribosome proofreading mechanisms to maintain intact the fidelity of genetic information flow. Despite this, low level gene translational errors induced by mutations and environmental factors cause neurodegeneration and premature death in mice and mitochondrial disorders in humans. Paradoxically, such errors can generate advantageous phenotypic diversity in fungi and bacteria through poorly understood molecular processes.ResultsIn 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.ConclusionsWe 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.

Proteome complexity and the forces that drive proteome imbalance

“…Decreases in fidelity are also undesirable: in the yeast Saccharomyces cerevisiae , the introduction of a transfer RNA that miscodes a leucine codon as serine results in the chronic mistranslation of the entire transcriptome 45 . This reduction in fidelity produces a transcriptional response that resembles the environmental stress response, as well as a decrease in ribosomal protein mRNAs, a decrease in the overall rates of protein synthesis and an overall reduction in fitness 45 . To survive, cells that have unstable genomes, such as cancer cells, might require compensatory adaptation to such prolonged activation of stress responses.…”

Translational fidelity and mistranslation in the cellular response to stress

“…For the cell, the consequences of aaRSs failing to discriminate between amino acids is potentially disastrous and could lead to mistranslation of proteins and activation of cellular stress responses 16 . The challenge to correctly recognize the 20 proteinogenic amino acids centres around their limited diversity in chemical space, which makes it difficult to accurately select substrates from a pool of structurally similar constituents 17 .…”

Roles of the tyrosine isomers meta- tyrosine and ortho- tyrosine in oxidative stress

“…Paredes et al studied the global effects of substituting serine for leucine—which have comparable amino acid hydrophobicity ranks to tyrosine and phenylalanine, respectively—and showed that even a low level of amino acid mistranslation that does not affect growth rate in yeast (~1%) is sufficient to up-regulate genes associated with oxidative stress, ER stress, and heat shock while down-regulating genes related to protein synthesis. At the same time the enzymatic activity of specific proteins was reduced, and protein aggregation increased (Paredes et al, 2012). It is therefore possible that the resulting substitution of a polar tyrosine isomer for non-polar phenylalanine during protein synthesis produces adverse changes to protein structure and activity and elicits various downstream cellular response pathways, including activation of the unfolded protein response, the heat shock response, augmented proteasome activity, and/or promotion of apoptosis.…”