title: Evolution of Robustness to Protein Mistranslation by Accelerated Protein Turnover.
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.
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Dorottya
authors.initials: D
authors.lastname: Kalapis
authors.affiliation: Institute for Biomedicine-iBiMED, Health Sciences, University of Aveiro, Aveiro, Portugal.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Bezerra
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Farkas
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Horvath
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Bódi
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Andreea
authors.initials: A
authors.lastname: Daraba
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Béla
authors.initials: B
authors.lastname: Szamecz
authors.affiliation: Centro Nacional de Análises Genómico, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Ivo
authors.initials: I
authors.lastname: Gut
authors.affiliation: Centro Nacional de Análises Genómico, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Bayes
authors.affiliation: Institute for Biomedicine-iBiMED, Health Sciences, University of Aveiro, Aveiro, Portugal.
authors.forename: Manuel A S
authors.initials: MA
authors.lastname: Santos
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Pál
mesh_terms: D000222:Adaptation, Physiological; D002176:Candida albicans / Q000201:enzymology / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D003062:Codon; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D015966:Gene Expression Regulation, Fungal; D016681:Genome, Fungal; D008957:Models, Genetic; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000201:enzymology / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic; D013312:Stress, Physiological; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D003062:Codon; D005656:Fungal Proteins; D020543:Proteome; D029701:Saccharomyces cerevisiae Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex