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Metal ions are essential components for the survival of living organisms. For most species, intracellular and extracellular ionic conditions differ significantly. As G-quadruplexes (G4s) are ion-dependent structures, changes in the [Na+]/[K+] ratio may affect the folding of genomic G4s. More than 11000 putative G4 sequences in the human genome (hg19) contain at least two runs of three continuous cytosines, and these mixed G/C-rich sequences may form a quadruplex or a competing hairpin structure based on G-C base pairing. In this study, we examine how the [Na+]/[K+] ratio influences the structures of G/C-rich sequences. The natural G4 structure with a 9-nt long central loop, CEBwt, was chosen as a model sequence, and the loop bases were gradually replaced by cytosines. The series of CEB mutations revealed that the presence of cytosines in G4 loops does not prevent G4 folding or decrease G4 stability but increases the probability of forming a competing structure, either a hairpin or an intermolecular duplex. Slow conversion to the quadruplex in vitro (in a potassium-rich buffer) and cells was demonstrated by NMR. 'Shape-shifting' sequences may respond to [Na+]/[K+] changes with delayed kinetics., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A G-rich sequence found in the regulatory region of the RANKL gene, which is associated with homeostasis of bone metabolism, folds into a two-quartet basket-type G-quadruplex stabilized by A⋅G⋅A and G⋅G⋅G base-triads. Perusal of local structural features together with G/A-to-T modifications uncovered the critical role of A5 for the formation of a distinct antiparallel two-quartet topology and not the three-quartet topology that would be expected based on the sequence with four GGG-tracts alone. The structural changes induced by the A5-to-T5 modification include a switch in orientation and relative positions of G-strands that together with anti to syn reorientation of G12 provide insights into the complexity of the interactions that influence the folding of G-rich DNA. Understanding the impact of loop residues on the stability and formation of G-quadruplexes advances our knowledge and ability to predict structures adopted by G-rich sequences, which are involved in regulatory mechanisms in the cell, and may also facilitate drug design., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A G‐rich sequence found in the regulatory region of the RANKL gene, which is associated with homeostasis of bone metabolism, folds into a two‐quartet basket‐type G‐quadruplex stabilized by A⋅G⋅A and G⋅G⋅G base‐triads. Perusal of local structural features together with G/A‐to‐T modifications uncovered the critical role of A5 for the formation of a distinct antiparallel two‐quartet topology and not the three‐quartet topology that would be expected based on the sequence with four GGG‐tracts alone. The structural changes induced by the A5‐to‐T5 modification include a switch in orientation and relative positions of G‐strands that together with anti to syn reorientation of G12 provide insights into the complexity of the interactions that influence the folding of G‐rich DNA. Understanding the impact of loop residues on the stability and formation of G‐quadruplexes advances our knowledge and ability to predict structures adopted by G‐rich sequences, which are involved in regulatory mechanisms in the cell, and may also facilitate drug design. Let's switch a fold: A G‐rich sequence found in the regulatory region of the RANKL gene, which is associated with homeostasis of bone metabolism, folds into a two‐quartet basket‐type G‐quadruplex stabilized by A⋅G⋅A and G⋅G⋅G base‐triads. A5 is critical for the formation of the distinct antiparallel two‐quartet topology and not the three‐quartet topology that would be expected based on a sequence with four GGG‐tracts alone. [ABSTRACT FROM AUTHOR]

Specific loop interactions involving an adenine residue can critically influence the folding pathway and structure of a G‐quadruplex. In their Communication on page 15395 ff., J. Plavec and co‐workers show that a sequence with four GGG‐tracts folds into a G‐quadruplex with two quartets stabilized by A⋅G⋅A and G⋅G⋅G base‐triads. Modification of a single adenine modulates the loop interactions and leads to exciting structural changes including a two‐to‐three‐quartet structural switch. [ABSTRACT FROM AUTHOR]