Recent developments in genetic code engineering demonstrated that quadruplet codon could be used to encode unnatural amino acids (unAAs) under experimental conditions albeit with low decoding efficiency.  In nature, the programmed +1 frameshift (an apparent quadruplet codon decoding event) generally requires certain translational recoding signals that are embedded in the close proximity of the frameshift site on the mRNA.  In this work, we seek to mimic Nature’s strategy by identifying and introducing synthetic recoding signals into mRNA to boost the decoding efficiency of quadruplet codons.  Through searching a large sequence space, several strong recoding signals were obtained, which led to significantly elevated efficiency in quadruplet codon decoding.  Furthermore, signals that inhibit quadruplet codon decoding were also identified.  This work will facilitate the creation of an optimized and standardized system for the genetic incorporation of unnatural amino acids using quadruplet codons, which will augment current efforts in the synthesis of biopolymers that contain multiple unnatural building blocks.  Besides applications in genetic code expansion, our data will also provide insights into mechanisms of the quadruplet codon decoding process.

Identification of translational recoding signals for an improved quadruplet codon decoding

2019 Spring National Meeting

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