Please use this identifier to cite or link to this item: http://hdl.handle.net/10773/24428
Title: Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification
Author: Bezerra, Ana R.
Simões, João
Lee, Wanseon
Rung, Johan
Weil, Tobias
Gut, Ivo G.
Gut, Marta
Bayes, Mónica
Rizzetto, Lisa
Cavalieri, Duccio
Giovannini, Gloria
Bozza, Silvia
Romani, Luigina
Kapushesky, Misha
Moura, Gabriela R.
Santos, Manuel A. S.
Issue Date: 2013
Publisher: Elsevier
Abstract: Many 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.
Peer review: yes
URI: http://hdl.handle.net/10773/24428
DOI: 10.1073/pnas.1302094110
ISSN: 0027-8424
Publisher Version: http://www.pnas.org/cgi/doi/10.1073/pnas.1302094110
Appears in Collections:CESAM - Artigos
DBio - Artigos

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