The diverse structural landscape of quadruplexes

Abstract

G‐quadruplexes are secondary structures formed in G‐rich sequences in DNA and RNA. Considerable research over the past three decades has led to in‐depth insight into these unusual structures in DNA. Since the more recent exploration into RNA G‐quadruplexes, such structures have demonstrated their in cellulo existence, function and roles in pathology. In comparison to Watson‐Crick‐based secondary structures, most G‐quadruplexes display highly redundant structural characteristics. However, numerous reports of G‐quadruplex motifs/structures with unique features (e.g. bulges, long loops, vacancy) have recently surfaced, expanding the repertoire of G‐quadruplex scaffolds. This review addresses G‐quadruplex formation and structure, including recent reports of non‐canonical G‐quadruplex structures. Improved methods of detection will likely further expand this collection of novel structures and ultimately change the face of quadruplex‐RNA targeting as a therapeutic strategy.

Structure of a DNA G-Quadruplex Related to Osteoporosis with a G-A Bulge Forming a Pseudo-loop

“…DNA regions, rich in tracts of guanines intervened by short (usually 1–7 nucleotides long) random sequences, are prone to self-associate into four-stranded structures called G-quadruplexes [ 2 , 4 , 15 ]. G-rich sequences able to fold into G-quadruplex structures are not randomly dispersed throughout the genome, but enriched within regions associated with gene regulation, including promoters, introns and UTRs, and at the ends of the chromosomes, where they play an important role in telomere biology [ 13 , 14 , 16 , 17 , 18 , 19 , 20 ]. In specific localized environments the formation of non-canonical DNA structures can even be preferred over B DNA form [ 21 ].…”

“…The core of the G-quadruplex structure is composed of stacked G-quartets, Hoogsteen hydrogen-bonded planes of four guanines, which are connected by short random loop-forming sequences in different orientations. Due to various possible options of G-quartet geometries and several loop combinations, G-quadruplexes are considered to be a very polymorphic structural family [ 2 , 15 , 19 , 22 , 23 , 24 ]. Individual G-strand, one of the four pillars of the G-quadruplex scaffold, is usually established by sequentially successive guanines, which participate in the formation of consecutive G-quartets.…”

RNA G-quadruplex structures exist and function in vivo

“…One of such complex structures is RNA G-quadruplex (RG4), which is folded with guanine-rich (G-rich) sequences in vitro and consists of two or more layers of G-quartets involving both Hoogsteen and Watson-Crick base pairs 5,6 . RG4s can be very stable in vitro in the presence of ion cations such as potassium (K + ), therefore they are hypothesized to exist in vivo and to be involved in novel 40 functions 5 , such as post-transcriptional regulation of gene expression [7][8][9] . Nevertheless, the lack of direct evidences of RG4 folding in vivo raised the key question of whether all these suggested functions are due to RG4 structure or sequence motif.…”

“…RG4s are less stable (Tm ~ 14-30 °C ) 40,41 , thereby harbouring higher flexibility to switch between folded and unfolded states within the temperature range that most plants favour. This flexibility may facilitate a regulatory role in plant adaption to the immediate local environment.…”

“…As such, RG4 structures might contribute to maintaining an optimum potassium level in plants. Apart from potassium levels, temperature is another key factor that was suggested to affect the folding of RG4s in vitro 40,41 . The optimal environmental temperature for plants (21-22 °C for Arabidopsis and 26-28 °C for rice) is much lower than the body temperature of animals (37 °C for human and 36.6 °C for mice).…”