Folding dynamics of polymorphic G‐quadruplex structures

Abstract

G-quadruplexes (G4), found in numerous places within the human genome, are involved in essential processes of cell regulation. Chromosomal DNA G4s are involved for example, in replication and transcription as first steps of gene expression. Hence, they influence a plethora of downstream processes. G4s possess an intricate structure that differs from canonical B-form DNA. Identical DNA G4 sequences can adopt multiple long-lived conformations, a phenomenon known as G4 polymorphism. A detailed understanding of the molecular mechanisms that drive G4 folding is essential to understand their ambivalent regulatory roles.Disentangling the inherent dynamic and polymorphic nature of G4 structures thus is key to unravel their biological functions and make them amenable as molecular targets in novel therapeutic approaches. We here review recent experimental approaches to monitor G4 folding and discuss structural aspects for possible folding pathways. Substantial progress in the understanding of G4 folding within the recent years now allows drawing comprehensive models of the complex folding energy landscape of G4s that we herein evaluate based on computational and experimental evidence.

Phen‐DC3 Induces Refolding of Human Telomeric DNA into a Chair‐Type Antiparallel G‐Quadruplex through Ligand Intercalation

“…[ 25 , 26 , 27 ] The polymorphism arises from differences in strand stoichiometry, position and conformation of the loops connecting Gs and mutual orientations of G‐tracts in the core of the structure. [28] The archetypal polymorphic sequence is the human telomeric repeat sequence (TTAGGG) n , for which diverse (parallel, antiparallel and hybrid) intramolecular folding topologies have been identified (Figure 1 ). [ 22 , 24 , 29 , 30 , 31 , 32 , 33 , 34 ]…”

G4-quadruplex-binding proteins: review and insights into selectivity

“…Formation and degradation of G4Qs have been shown in vitro to be dependent on a number of intrinsic factors including loop length, leading nucleic acids and incorporated ions (Bhattacharyya et al 2016 ; Chen et al 2021 ; Guédin et al 2010 ; Hazel et al 2004 ; Piazza et al 2015 ). While it is possible that in vivo G4Qs are influenced by the same factors, there is the of course the additional interplay with many cellular proteins, namely, G4-binding proteins whose roles and influences are still being defined.…”

“…G4Q stability is inversely linked to loop length—the shorter the loop, the more stable the G4Q. Guedin et al performed a nice systematic assessment of this whereby they studied the melting temperatures ( Tm ) of a large panel of G4Q with varying loop lengths, showing that a length greater than 9 nt had a destabilizing effect on the structure, especially if multiple longer length loops were incorporated (Guédin et al 2010 ). The c-MYC promoter G4Q is an example of a highly stable, short loop-length G4Q, while the TRA2β has a single 8-nt loop (Table 1 ).…”

Polymorphic and Higher-Order G-Quadruplexes as Possible Transcription Regulators: Novel Perspectives for Future Anticancer Therapeutic Applications

“…As anticipated, the dissection of the G-quadruplex folding landscape is a relevant piece of information when mapping the structural evolution of PQS in the nuclear environment. Indeed, folding intermediates, which are structurally distinct from the characterized thermodynamically favored species, could show half-life times compatible with the timescale of physiological processes [ 39 ]. Considering this aspect, we cannot rule out that the control of biological functions in the cell might be driven by the kinetically favored G4s, rather than the more thermodynamically stable G4s.…”