期刊
NATURE METHODS
卷 13, 期 5, 页码 453-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NMETH.3807
关键词
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资金
- US National Institutes of Health (NIH) [R01 GM090126, R01 AI110794]
- Center for Topology of Cancer Evolution and Heterogeneity (NIH) [U54 CA193313]
- US National Institutes of Health [F30 CA174357, S10RR027050]
- TL1 Precision Medicine fellowship [5TL1 TR000082]
Protein synthesis in eukaryotes is regulated by diverse reprogramming mechanisms that expand the coding capacity of individual genes. Here, we exploit one such mechanism, termed -1 programmed ribosomal frameshifting (-1 PRF), to engineer ligand-responsive RNA switches that regulate protein expression. First, efficient -1 PRF stimulatory RNA elements were discovered by in vitro selection; then, ligand-responsive switches were constructed by coupling -1 PRF stimulatory elements to RNA aptamers using rational design and directed evolution in Saccharomyces cerevisiae. We demonstrate that -1 PRF switches tightly control the relative stoichiometry of two distinct protein outputs from a single mRNA, exhibiting consistent ligand response across whole populations of cells. Furthermore, -1 PRF switches were applied to build single-mRNA logic gates and an apoptosis module in yeast. Together, these results showcase the potential for harnessing translation-reprogramming mechanisms for synthetic biology, and they establish -1 PRF switches as powerful RNA tools for controlling protein synthesis in eukaryotes.
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