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dc.contributor.authorBezerra, Ana R.pt_PT
dc.contributor.authorSimões, Joãopt_PT
dc.contributor.authorLee, Wanseonpt_PT
dc.contributor.authorRung, Johanpt_PT
dc.contributor.authorWeil, Tobiaspt_PT
dc.contributor.authorGut, Ivo G.pt_PT
dc.contributor.authorGut, Martapt_PT
dc.contributor.authorBayes, Mónicapt_PT
dc.contributor.authorRizzetto, Lisapt_PT
dc.contributor.authorCavalieri, Ducciopt_PT
dc.contributor.authorGiovannini, Gloriapt_PT
dc.contributor.authorBozza, Silviapt_PT
dc.contributor.authorRomani, Luiginapt_PT
dc.contributor.authorKapushesky, Mishapt_PT
dc.contributor.authorMoura, Gabriela R.pt_PT
dc.contributor.authorSantos, Manuel A. S.pt_PT
dc.description.abstractMany fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research.pt_PT
dc.description.sponsorshipWe thank Alexander Johnson for providing the C. albicans strains and plasmids and Judith Berman, Csaba Pál, and Dieter Söll for their useful comments and suggestions on the manuscript. The study was funded by the European Union Framework Program 7 (EUFP7) Sybaris Consortium Project 242220 and the Portuguese Science Foundation through Fundo Europeu de Desenvolvimento Regional (FEDER/FCT) Project PTDC/BIA-MIC/099826/2008.pt_PT
dc.titleReversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversificationpt_PT
degois.publication.titleProceedings of the National Academy of Sciencespt_PT
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