Abstract
Understanding the mechanism of Na+/K+-dependent spectral conversion of human telomeric G-quadruplex (G4) sequences has been limited not only because of the structural polymorphism but also the lack of sufficient structural information at different stages along the conversion process for one given oligonucleotide. In this work, we have determined the topology of the Na+ form of Tel23 G4, which is the same hybrid form as the K+ form of Tel23 G4 despite the distinct spectral patterns in their respective nuclear magnetic resonance (NMR) and circular dichroism spectra. The spectral difference, particularly the well-resolved imino proton NMR signals, allows us to monitor the structural conversion from Na+ form to K+ form during Na+/K+ exchange. Time-resolved NMR experiments of hydrogen–deuterium exchange and hybridization clearly exclude involvement of the global unfolding for the fast Na+/K+ spectral conversion. In addition, the K+ titration monitored by NMR reveals that the Na+/K+ exchange in Tel23 G4 is a two-step process. The addition of K+ significantly stabilizes the unfolding kinetics of Tel23 G4. These results offer a possible explanation of rapid spectral conversion of Na+/K+ exchange and insight into the mechanism of Na+/K+ structural conversion in human telomeric G4s.
Highlights
A G-rich single stranded DNA of telomere can form various G4 structures through Hoogsteen hydrogen bonds in the presence of monovalent cations such as Na+ or K+ [1,2]
A nuclear magnetic resonance (NMR) study showed that Tel22, a 22-nt human telomeric sequence, d[AG3(T2AG3)3], forms an antiparallel basket G4 structure in Na+ solution [15], while X-ray crystallography showed that the same sequence adopts a parallel propeller G4 structure in presence of K+ condition [16]
In this work, we have determined the topology of the Na+ form of Tel23 G4 to be the same hybrid form as the K+ form of Tel23
Summary
A G-rich single stranded DNA of telomere can form various G4 structures through Hoogsteen hydrogen bonds in the presence of monovalent cations such as Na+ or K+ [1,2] Such G4 structures have been shown to potentially exist in human chromosome end [3,4,5,6,7], exhibiting the ability to inhibit telomerase activity and are potential targets for anticancer drug design [8,9,10,11]. A newly resolved structure of human telomere G4, Tel (d[TTAG3(T2AG3)3TTA]), has been found to adopt a (2+2) topology with two lateral and one double reversal loops in Na+ solution [23] These findings exemplify the fact that slight sequence variations in human telomeres can result in diverse G4s with different folding topologies. Such structural diversities in human telomere G4s observed in vitro may possibly be present in vivo [24,25]
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