Abstract
Translational errors occur at high rates, and they influence organism viability and the onset of genetic diseases. To investigate how organisms mitigate the deleterious effects of protein synthesis errors during evolution, a mutant yeast strain was engineered to translate a codon ambiguously (mistranslation). It thereby overloads the protein quality-control pathways and disrupts cellular protein homeostasis. This strain was used to study the capacity of the yeast genome to compensate the deleterious effects of protein mistranslation. Laboratory evolutionary experiments revealed that fitness loss due to mistranslation can rapidly be mitigated. Genomic analysis demonstrated that adaptation was primarily mediated by large-scale chromosomal duplication and deletion events, suggesting that errors during protein synthesis promote the evolution of genome architecture. By altering the dosages of numerous, functionally related proteins simultaneously, these genetic changes introduced large phenotypic leaps that enabled rapid adaptation to mistranslation. Evolution increased the level of tolerance to mistranslation through acceleration of ubiquitin-proteasome–mediated protein degradation and protein synthesis. As a consequence of rapid elimination of erroneous protein products, evolution reduced the extent of toxic protein aggregation in mistranslating cells. However, there was a strong evolutionary trade-off between adaptation to mistranslation and survival upon starvation: the evolved lines showed fitness defects and impaired capacity to degrade mature ribosomes upon nutrient limitation. Moreover, as a response to an enhanced energy demand of accelerated protein turnover, the evolved lines exhibited increased glucose uptake by selective duplication of hexose transporter genes. We conclude that adjustment of proteome homeostasis to mistranslation evolves rapidly, but this adaptation has several side effects on cellular physiology. Our work also indicates that translational fidelity and the ubiquitin-proteasome system are functionally linked to each other and may, therefore, co-evolve in nature.
Highlights
Fidelity of protein synthesis has a substantial impact on cellular survival [1,2]
Fidelity of information transfer has a substantial impact on cellular survival, many steps in protein production are strikingly error-prone
Such errors during protein synthesis can have a substantial influence on viability and the onset of genetic diseases
Summary
Fidelity of protein synthesis has a substantial impact on cellular survival [1,2]. There might be incorporation of one amino acid for another (missense errors), premature termination of protein synthesis, frameshift errors and read-through of stop codons (nonsense errors). The average missense error rate during translation is between 10−3 and 10−4 [3]. While such estimates are rough and are based on a variety of methodologies, they clearly indicate that error rates during protein production are three to five orders of magnitude higher than DNA-replication errors. The exact amount is currently debated [4,5], it appears that a large fraction of the proteins in eukaryotic cells is defective. Most of these faulty proteins are degraded by the proteasome or aggregate [1]. Accuracy of translation has an optimal value reflecting a trade-off between costs of kinetic proofreading and cellular side consequences of erroneous protein accumulation
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