Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes

Abstract

By using all atom molecular dynamics simulations, we studied the behavior of human DNA telomere sequences in guanine quadruplex (G4) conformation and in the presence of oxidative lesions, namely abasic sites. In particular, we evidenced that while removing one guanine base induces a significant alteration and destabilization of the involved leaflet, human telomere oligomers tend, in most cases, to maintain at least a partial quadruplex structure, eventually by replacing the empty site with undamaged guanines of different leaflets. This study shows that (i) the disruption of the quadruplex leaflets induces the release of at least one of the potassium cations embedded in the quadruplex channel and that (ii) the electrostatic interactions of the DNA sequence with the aforementioned cations are fundamental to the maintenance of the global quadruplex structure.

Analytical and Structural Studies for the Investigation of Oxidative Stress in Guanine Oligonucleotides

“…This is in line with the earlier observations [1]. Hognon et al [68] have studied another possible consequence of epigenetic effects, namely the formation of the so-called abasic or apurinic/apyrimidinic (AP) site in the 22nt hTel sequence d(AG3(T2AG3)3) GQ structure that was examined by molecular dynamics. They distinguished eight The simulations also indicated some connection between loop and the external G4 layer; however, these stacking interactions have not been corroborated by NMR measurements.…”

“…Hognon et al [68] have studied another possible consequence of epigenetic effects, namely the formation of the so-called abasic or apurinic/apyrimidinic (AP) site in the 22nt hTel sequence d(AG3(T2AG3)3) GQ structure that was examined by molecular dynamics. They distinguished eight Hognon et al [68] have studied another possible consequence of epigenetic effects, namely the formation of the so-called abasic or apurinic/apyrimidinic (AP) site in the 22nt hTel sequence d(AG 3 (T 2 AG 3 ) 3 ) GQ structure that was examined by molecular dynamics. They distinguished eight instances according to the position of the AP site in the GQ structure, where four cases were related to the middle layer and four cases to the external layer.…”

“…Hognon et al [ 68 ] have studied another possible consequence of epigenetic effects, namely the formation of the so-called abasic or apurinic/apyrimidinic (AP) site in the 22nt hTel sequence d(AG 3 (T 2 AG 3 ) 3 ) GQ structure that was examined by molecular dynamics. They distinguished eight instances according to the position of the AP site in the GQ structure, where four cases were related to the middle layer and four cases to the external layer.…”

Targeting G-quadruplexes with Organic Dyes: Chelerythrine–DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy

“…Owing to the high amount of guanine constituting the G4 sequences, the latter represent obvious hot spots for oxidative lesions induced by external sensitizers and drugs. Important structural rearrangements [41], or even epigenetic related modulations [42] induced by G4 guanine oxidation, have been recently reported.…”

Forever Young: Structural Stability of Telomeric Guanine-Quadruplexes in Presence of Oxidative DNA Lesions

“…25,38,42 In a previous work we have analyzed by molecular modeling and simulation the effects of the presence of apurinic/apyrimidinic (AP) sites on the structure of h-Telo G4s. 43 We have pointed out that the G4 stability strongly depends on the position of the AP in the DNA sequence. While usually the damaged G4 structure has been shown to rearrange to maintain the global folded conformation, some cases can be evidenced in which the quadruplex structure is totally unfolded.…”