Synthetic biology tools for modulating gene expression in living cells have many biotechnological and therapeutic applications. Here we describe the design and engineering of split orthogonal aminoacyl-tRNA synthetases (o-aaRSs) to translationally control gene expression in bacteria and eukaryotes. These split o-aaRSs regulate gene expression by conditionally suppressing stop codons in the encoding mRNA. We show that gene expression can be activated using small molecule ligands as molecular switches that induce stop codon suppression. Further, we show that split o-aaRSs can serve as novel tools for detecting therapeutically relevant protein-protein interactions in cells, including those involved in cancer and SARS-CoV-2 infection. The use of split o-aaRSs to control gene expression in human cells will be described.

Split aminoacyl-tRNA synthetases for proximity-induced stop codon suppression

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