{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:22:10Z","timestamp":1772137330671,"version":"3.50.1"},"reference-count":51,"publisher":"Proceedings of the National Academy of Sciences","issue":"27","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,7,2]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    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\n                    <jats:italic>C. albicans<\/jats:italic>\n                    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\n                    <jats:italic>C. albicans<\/jats:italic>\n                    genome and open the door to produce microorganisms with genetic code alterations for basic and applied research.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1302094110","type":"journal-article","created":{"date-parts":[[2013,6,17]],"date-time":"2013-06-17T23:05:44Z","timestamp":1371510344000},"page":"11079-11084","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":85,"title":["Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification"],"prefix":"10.1073","volume":"110","author":[{"given":"Ana R.","family":"Bezerra","sequence":"first","affiliation":[{"name":"RNA Biology Laboratory, Department of Biology and Centre for Environmental and Marine Studies, University of Aveiro, 3810-193 Aveiro, Portugal;"}]},{"given":"Jo\u00e3o","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"RNA Biology Laboratory, Department of Biology and Centre for Environmental and Marine Studies, University of Aveiro, 3810-193 Aveiro, Portugal;"}]},{"given":"Wanseon","family":"Lee","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, United Kingdom;"}]},{"given":"Johan","family":"Rung","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, United Kingdom;"}]},{"given":"Tobias","family":"Weil","sequence":"additional","affiliation":[{"name":"RNA Biology Laboratory, Department of Biology and Centre for Environmental and Marine Studies, University of Aveiro, 3810-193 Aveiro, Portugal;"}]},{"given":"Ivo G.","family":"Gut","sequence":"additional","affiliation":[{"name":"Centro Nacional de An\u00e1lises Gen\u00f3mico, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain;"}]},{"given":"Marta","family":"Gut","sequence":"additional","affiliation":[{"name":"Centro Nacional de An\u00e1lises Gen\u00f3mico, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain;"}]},{"given":"M\u00f3nica","family":"Bay\u00e9s","sequence":"additional","affiliation":[{"name":"Centro Nacional de An\u00e1lises Gen\u00f3mico, Parc Cient\u00edfic de Barcelona, 08028 Barcelona, Spain;"}]},{"given":"Lisa","family":"Rizzetto","sequence":"additional","affiliation":[{"name":"Research and Innovation Center, Fondazione E. Mach, 38010 San Michele all\u2019Adige, Italy;"}]},{"given":"Duccio","family":"Cavalieri","sequence":"additional","affiliation":[{"name":"Research and Innovation Center, Fondazione E. Mach, 38010 San Michele all\u2019Adige, Italy;"},{"name":"Department of Neurofarba, University of Florence, 50139 Florence, Italy; and"}]},{"given":"Gloria","family":"Giovannini","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, Section of Microbiology, University of Perugia, 06126 Perugia, Italy"}]},{"given":"Silvia","family":"Bozza","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, Section of Microbiology, University of Perugia, 06126 Perugia, Italy"}]},{"given":"Luigina","family":"Romani","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, Section of Microbiology, University of Perugia, 06126 Perugia, Italy"}]},{"given":"Misha","family":"Kapushesky","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton CB10 1SD, United Kingdom;"}]},{"given":"Gabriela R.","family":"Moura","sequence":"additional","affiliation":[{"name":"RNA Biology Laboratory, Department of Biology and Centre for Environmental and Marine Studies, University of Aveiro, 3810-193 Aveiro, Portugal;"}]},{"given":"Manuel A. 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