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Reeling in microorganisms – Nature Chemical Biology

The metabolic engineering of microorganisms is an attractive platform for bioremediation and the industrial production of chemicals. However, biocontainment strategies are needed if genetically modified organisms are to be released into open environments. Hoffmann and Cai report a biocontainment strategy in yeast based on targeted protein degradation.

The authors performed high-throughput screening to identify genes that, when fused to an estrogen receptor-derived degron (ERdd), made Saccharomyces cerevisiae dependent on the hormone estradiol. Estradiol stabilizes the ERdd fusion protein, preventing its degradation. They identified three top strains expressing the genes SPC110–ERdd, RRP46–ERdd and DIS3–ERdd that were strictly dependent on estradiol. The growth of a strain with both SPC110–ERdd and RRP46–ERdd could be restored to the fitness level of the wild-type parental strain when treated with 100 nM estradiol. The wild-type strain did not outcompete the engineered strains over 100 generations, suggestive of their evolutionary stability, which is crucial for open-environment applications. Analysis of strains able to escape biocontainment showed mutations in fusion proteins that inactivate the ERdd and in proteins that affect regulation of the proteasome.