RNA G-quadruplexes: emerging mechanisms in disease

Abstract

RNA G-quadruplexes (G4s) are formed by G-rich RNA sequences in protein-coding (mRNA) and non-coding (ncRNA) transcripts that fold into a four-stranded conformation. Experimental studies and bioinformatic predictions support the view that these structures are involved in different cellular functions associated to both DNA processes (telomere elongation, recombination and transcription) and RNA post-transcriptional mechanisms (including pre-mRNA processing, mRNA turnover, targeting and translation). An increasing number of different diseases have been associated with the inappropriate regulation of RNA G4s exemplifying the potential importance of these structures on human health. Here, we review the different molecular mechanisms underlying the link between RNA G4s and human diseases by proposing several overlapping models of deregulation emerging from recent research, including (i) sequestration of RNA-binding proteins, (ii) aberrant expression or localization of RNA G4-binding proteins, (iii) repeat associated non-AUG (RAN) translation, (iv) mRNA translational blockade and (v) disabling of protein-RNA G4 complexes. This review also provides a comprehensive survey of the functional RNA G4 and their mechanisms of action. Finally, we highlight future directions for research aimed at improving our understanding on RNA G4-mediated regulatory mechanisms linked to diseases.

Figure 1.

Overview of RNA G4s: position, proposed function and link with disease.

Figure 2.

Mechanisms of action underlying the function of RNA G4s. RNA G4 binding to RBP (A), RBP binding to both DNA and RNA G4 (B), intermolecular G4 formed by DNA and RNA strands (C), equilibrium between RNA G4 and hairpin conformation (D), RNA G-rich sequence that can fold into a G4 or hybridize with the C-rich template DNA strand in the R-loop structure (E).

Figure 3.

RNA G4s and cancer hallmarks. Examples of RNA G4-containing genes that have been implicated in regulation of each of the hallmarks of cancer.

Figure 4.

Mechanistic models supporting the proposed link between RNA G4s and human diseases. Based on different examples of RNA G4 associated with disease, five mechanisms of action can be delineated: sequestration of RNA G4-binding proteins impacting the nucleolar function or the regulation of post-transcriptional processes (A), non-AUG (RAN) translation giving raise to toxic peptides (B), altered expression of RNA G4-binding proteins linked to RBP loss (i), RBP overexpression (ii) or RBP mislocalization (iii) (C), translational block by runs of adjacent G-repeats (D) and disabled RNA G4-protein complexes due to mutations (depicted by a red star) in RNA G4s (i) or in RBPs (ii) (E).