5'-UTR RNA G-quadruplexes: translation regulation and targeting

Abstract

RNA structures in the untranslated regions (UTRs) of mRNAs influence post-transcriptional regulation of gene expression. Much of the knowledge in this area depends on canonical double-stranded RNA elements. There has been considerable recent advancement of our understanding of guanine(G)-rich nucleic acids sequences that form four-stranded structures, called G-quadruplexes. While much of the research has been focused on DNA G-quadruplexes, there has recently been a rapid emergence of interest in RNA G-quadruplexes, particularly in the 5'-UTRs of mRNAs. Collectively, these studies suggest that RNA G-quadruplexes exist in the 5'-UTRs of many genes, including genes of clinical interest, and that such structural elements can influence translation. This review features the progresses in the study of 5'-UTR RNA G-quadruplex-mediated translational control. It covers computational analysis, cell-free, cell-based and chemical biology studies that have sought to elucidate the roles of RNA G-quadruplexes in both cap-dependent and -independent regulation of mRNA translation. We also discuss protein trans-acting factors that have been implicated and the evidence that such RNA motifs have potential as small molecule target. Finally, we close the review with a perspective on the future challenges in the field of 5'-UTR RNA G-quadruplex-mediated translation regulation.

Figure 1.

Schematic representations of (A) a G-quartet arrangement, (B) a G-quadruplex nucleic acids structure and (C) the intermolecular hydrogen bonding network (dash lines) between the ribose C2′ hydroxyl groups and the O4′ sugar oxygens of RNA G-quartet-forming residues [adapted from (53), PDB: 3IBK].

Figure 2.

Schematic illustration of the possible roles of 5′-UTR RNA G-quadruplex formation in cap-dependent and cap-independent regulation of translation initiation. Red light indicates translation inhibition. Green light indicates translation enhancement.

Figure 3.

Chemical structures of synthetic molecules that have been demonstrated to exert selective RNA G-quadruplex mediated translation inhibition.