The importance of being modified: an unrealized code to RNA structure and function

A, U, C, and G are boring. Truly, four nucleosides sometimes repeated in seemingly endless sequence has a numbing effect even in a computational and structural context. However, there is nothing boring about the chemistries and structures of post-transcriptional modifications of RNA as indicated by the rising interest and rapidly increasing numbers of publications. A plethora of papers demonstrate that modified nucleosides of RNA are functionally indispensable for RNA processing and translation. Over the last 20 years, efficiency, accuracy, enhanced activity and responsiveness are terms that accompany studies of modifications. Modifications are found in all types of RNAs, in every structural motif and in unstructured regions. The large numbers of modifications in tRNAs are quite familiar. The presence, chemistries and RNA sequence locations of modified nucleosides are only now beginning to be appreciated as both temporal—in response to environmental (internal and external) signals—and spatial, in their effect on RNA conformation, dynamics, and functions. Modifications can be recognition determinants for proteins as well as incredible determiners of RNA structure and function. Unfortunately, we tend to neglect the modified nucleosides. Using amplification and transcription in vitro that disregard the native modified nucleosides, we study the interesting low abundance, non-coding RNAs for which one molecule per cell is sometimes enough to affect gene expression. On the other hand, we lack technologies sensitive enough to explore modifications and their functions in these same low abundance RNAs. Our lack of understanding of RNA modification regrettably limits innovation in the use of modified nucleosides for synthetic biology and medicine. However, the past two decades have led to some of the most interesting of findings.