Polymorphism of human telomeric quadruplex structures

Abstract

Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG). Compounds that can stabilize the intramolecular DNA G-quadruplexes formed in the human telomeric sequence have been shown to inhibit the activity of telomerase and telomere maintenance, thus the telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention. Knowledge of intramolecular human telomeric G-quadruplex structure(s) formed under physiological conditions is important for structure-based rational drug design and thus has been the subject of intense investigation. This review will give an overview of recent progress on the intramolecular human telomeric G-quadruplex structures formed in K + solution. It will also give insight into the structure polymorphism of human telomeric sequences and its implications for drug targeting.

Targeting G-Quadruplex DNA with Small Molecules

“…[58,90] It is important to note, however, that G-quadruplexes are highly dynamic structures and losses in DNA conformational entropy upon ligand binding might be an important factor in determining specificity. G-quadruplexes that exist as a dynamic mixture of conformations in the unbound state, like the human telomeric sequence, [91] should generally exhibit lower ligand affinities as compared to G-quadruplexes that adopt a single conformation. [58,90] While a large number of G-quadruplex ligands have been reported in the literature, [41,42,46,89,[92][93][94] the cationic porphyrin TMPyP4 (Fig.…”

Differential Effects of the G-Quadruplex Ligand 360A in Human Normal and Cancer Cells

“…However compounds that stabilize the telomeric G-quadruplex have been shown to inhibit the activity of telomerase and disrupt telomere capping and maintenance, making the human telomeric DNA G-quadruplex also an attractive target for cancer therapeutic intervention (Mergny & Helene, 1998;Riou et al, 2002;Gowan et al, 2001;de Cian et al, 2008). Indeed, the intramolecular telomeric G-quadruplex (Neidle & Parkinson, 2003;Dai et al, 2008) has been considered to be an attractive target for anticancer drug design since quadruplex ligands were found to inhibit telomerase (Sun et al, 1997;Zahler et al, 1991;Zaug et al, 2005). However genomic analyses using several algorithms have revealed that more than 370 000 sequences have the potential to form G-quadruplex structure in the human genome Huppert, 2008).…”

“…However, this result might be an underestimation of this binding because not all the decays can be detected by this method. In vitro studies have indicated the polymorphic nature of the telomeric G-quadruplex (Dai et al, 2008), and the 3 H-360A ligand may therefore be unable to bind all the G-quadruplex structural conformations. In addition, 3 H-360A is naturally unstable due to progressive radiolysis, so we cannot totally exclude a partial degradation of this G-quadruplex ligand.…”

“…Nevertheless, we cannot at this stage exclude G-quadruplex structure variation and/or the differential regulation of G-quadruplexes during cell cycle progression between normal and cancer cells In vitro studies using oligonucleotides have given some insights into the structural polymorphisms of the G-quadruplex. (Hurley, 2002;Bates et al, 2007;Oganesian & Bryan, 2007;Dai et al, 2008). These polymorphisms and the dynamic equilibrium of telomeric Gquadruplexes, between human normal and cancer cells, may be important for considerations for the design of future therapeutic interventions.…”

Potassium increases the antitumor effects of ascorbic acid in breast cancer cell lines in vitro

“…Furthermore, K + is essential to fold and stabilize G-quadruplexes (23). Agents that stabilize or target G-quadruplexes may act as anti-tumor agents (24); thus, physiological concentrations of K + are likely to be required for normal cell behavior (25,26). K ascorbate has been proposed as an anti-degenerative agent (27).…”