Deciphering the Enigmatic Biological Functions of RNA Guanine-Quadruplex Motifs in Human Cells.

Abstract

Guanine-rich sequences in nucleic acids can form noncanonical structures known as guanine quadruplexes (G-quadruplexes), which constitute a not yet fully elucidated layer of regulatory function for central cellular processes. RNA G-quadruplexes have been shown to be involved in the modulation of translation, the regulation of (alternative) splicing, and the subcellular transport of mRNAs, among other processes. However, in living cells, an equilibrium between the formation of G-quadruplex structures and their unwinding by RNA helicases is likely. The extent to which G-rich sequences adopt G-quadruplex structures in living eukaryotic cells is currently a matter of debate. Multiple lines of evidence confirm the intracellular formation of G-quadruplex structures, such as their detection by immunochemical approaches, fluorogenic probes, and in vivo nuclear magnetic resonance. However, intracellular chemical probing suggests most if not all are in an unfolded state. It is therefore tempting to speculate that some G-quadruplex structures are only temporarily formed when they are required to contribute to the fine-tuning of the processes mentioned above. Future research should focus on the analysis of G-quadruplex formation under physiological conditions, which will allow the re-evaluation of the biological function of G-quadruplex motifs in regulatory processes in their natural environment and at physiological expression levels. This will help in the elucidation of their significance in the regulation of central processes in molecular biology and the exploitation of their potential as therapeutic targets.