Adding to the Genetic Script: Extra Letters for New Functions

Oligonucleotides, both RNA and DNA, are fundamental to life despite being composed of a limited set of simple molecular building blocks. Chemists have long strived to add additional components, especially orthogonal, unnatural base pairs (UBPs). These increase the informational content of nucleic acids and provide site-specific anchors for labelling, enabling applications in aptamer enhancement, RNA structure elucidation, pathway tracing, sequencing, and the construction of semi-synthetic organisms. For this, suitable enzymes and techniques are required to incorporate and later analyse expanded alphabet genetic material. In this review we aim to outline some challenges, achievements, and possibilities that this field encompasses.