Transcription Regulation Through Nascent RNA Folding

Folding of RNA into secondary structures through intramolecular base pairing determines an RNA's three-dimensional architecture and associated function. Simple RNA structures like stem loops can provide specialized functions independent of coding capacity, such as protein binding, regulation of RNA processing and stability, stimulation or inhibition of translation. RNA catalysis is dependent on tertiary structures found in the ribosome, tRNAs and group I and II introns. While the extent to which non-coding RNAs contribute to cellular maintenance is generally appreciated, the fact that both non-coding and coding RNA can assume relevant structural states has only recently gained attention. In particular, the co-transcriptional folding of nascent RNA of all classes has the potential to regulate co-transcriptional processing, RNP (ribonucleoprotein particle) formation, and transcription itself. Riboswitches are established examples of co-transcriptionally folded coding RNAs that directly regulate transcription, mainly in prokaryotes. Here we discuss recent studies in both prokaryotes and eukaryotes showing that structure formation may carry a more widespread regulatory logic during RNA synthesis. Local structures forming close to the catalytic center of RNA polymerases have the potential to regulate transcription by reducing backtracking. In addition, stem loops or more complex structures may alter co-transcriptional RNA processing or its efficiency. Several examples of functional structures have been identified to date, and this review provides an overview of physiologically distinct processes where co-transcriptionally folded RNA plays a role. Experimental approaches such as single-molecule FRET and in vivo structural probing to further advance our insight into the significance of co-transcriptional structure formation are discussed.