Genetic alphabet expansion biotechnology by creating unnatural base pairs

•Unnatural base pairs that function as a third base pair in the central dogma were developed.•High-affinity DNA aptamers that specifically bind to target proteins and cells were generated.•Semi-synthetic organisms with six-base DNA were created.

Recent studies have made it possible to expand the genetic alphabet of DNA, which is originally composed of the four-letter alphabet with A-T and G-C pairs, by introducing an unnatural base pair (UBP). Several types of UBPs function as a third base pair in replication, transcription, and/or translation. Through the UBP formation, new components with different physicochemical properties from those of the natural ones can be introduced into nucleic acids and proteins site-specifically, providing their increased functionalities. Here, we describe the genetic alphabet expansion technology by focusing on three types of UBPs, which were recently applied to the creations of DNA aptamers that bind to proteins and cells and semi-synthetic organisms containing DNAs with a six-letter alphabet.

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