The emerging structural complexity of G-quadruplex RNAs

Abstract

G-quadruplexes (G4s) are four-stranded nucleic acid structures that arise from the stacking of Gquartets, cyclic arrangements of four guanines engaged in Hoogsteen base pairing. Until recently, most RNA G4 structures were thought to conform to a sequence pattern in which guanines stacking within the G4 would also be contiguous in sequence (e.g., four successive guanine trinucleotide tracts separated by loop nucleotides). Such a sequence restriction, and the stereochemical constraints inherent to RNA (arising, in particular, from presence of the 2'-OH), dictate relatively simple RNA G4 structures. Recent crystallographic and solution NMR structure determinations of a number of in vitro selected RNA aptamers has revealed RNA G4 structures of unprecedented complexity. Structures of the Sc1 aptamer that binds an RGG peptide from the Fragile-X Mental Retardation protein, various fluorescence turn-on aptamers (Corn, Mango, and Spinach), and the spiegelmer that binds the complement protein C5a, in particular, reveal complexity hitherto unsuspected in RNA G4s, including nucleotides in syn conformation, locally inverted strand polarity, and nucleotide quartets that are not all-G. Common to these new structures, the sequences folding into G4s do not conform to the requirement that guanine stacks arise from consecutive (contiguous in sequence) nucleotides. This review highlights how emancipation from this constraint drastically expands the structural possibilities of RNA G-quadruplexes.

Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating and highlights a critical role for sodium ions.

“…While suggesting a functional relevance for these QGRS, they might instead encode a critical sequence in the corresponding polyprotein as an alternative reason for their strict maintenance, which remains to be investigated. Atypical RNA GQs such as those with a bulged out nucleotide or a vacancy will escape our analysis, but there are currently only a few reports on their existence and possible role 48 .…”

“…CD is a gold standard to determine the strand orientations of GQs. These might be parallel, as commonly adopted by RNA and DNA, or anti-parallel and hybrid, which, with a few exceptions 48 , are observed only for DNA. Telomeric-repeatcontaining RNA (miniTERRA; Table 1), which adopts a three-layer parallel conformation 49 , served as a positive control.…”

Detecting and Profiling Endogenous RNA G-Quadruplexes in the Human Transcriptome

“…Increasing evidence has emphasized the important biological role of RNA G-quadruplexes and their close relationship with certain diseases [ 27 , 28 ], and we hope that more robust techniques can be developed to detect RNA G-quadruplexes with diverse complex structures [ 29 ] in vivo, or even at the single-cell level.…”

Rhodamine 6G-Ligand Influencing G-Quadruplex Stability and Topology

“…G-quadruplexes (G4s) are relatively common in the genomes of all living cells, including viruses, but their frequency differs from species to species [ 1 , 2 ]. The G4 motif may be an integral part of some artificially developed DNA and RNA aptamers [ 3 , 4 , 5 , 6 ]. The dispersion of putative G4 sequences in genomes is not random, however, and their localization is closely correlated with specific gene functions [ 7 ].…”