Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “quadruplex”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 289 records · Page 16Linked to original sources
PubMed1994

Stabilization of tetrahelical DNA by the quadruplex DNA binding protein QUAD.

The 57-kDa hepatic nuclear protein QUAD binds tightly and specifically a parallel tetrahelical form of the IgG switch region DNA (Weisman-Shomer, P. and Fry, M. (1993) J. Biol Chem. 268, 3306-3312). Here we show that QUAD is a heat-stable protein, maintaining approximately 90% of its tetrahelix binding activity after 10 min at 100 degrees C and becoming fully inactivated only after 30 min at 100 degrees C. To demonstrate that QUAD protects bound quadruplex DNA, naked and QUAD-bound tetrahelices were boiled, the protein residue in the complex was digested with trypsin and quadruplex and single-strand forms of the DNA component were resolved by electrophoresis. Whereas naked quadruplex DNA became fully denatured after 2 min at 100 degrees C, 55% of the QUAD-bound DNA was conserved as a tetrahelix after 6 min at 100 degrees C. These findings support the proposal that QUAD may act in vivo to stabilize tetrahelical DNA.

Base Sequence↗
PubMed2006

Natural and synthetic G-quadruplex interactive berberine derivatives.

The interaction of the natural alkaloid berberine with various G-quadruplex DNA structures and its ability to inhibit telomerase have been examined and compared with those of a synthetic piperidino derivative and the related compound coralyne. The results show that these molecules have selectivity for G-quadruplex compared to duplex DNA, and that their aromatic moieties play a dominant role in quadruplex binding.

Antineoplastic Agents↗
PubMed2000

G-quadruplex DNA: a potential target for anti-cancer drug design.

In addition to the familiar duplex DNA, certain DNA sequences can fold into secondary structures that are four-stranded; because they are made up of guanine (G) bases, such structures are called G-quadruplexes. Considerable circumstantial evidence suggests that these structures can exist in vivo in specific regions of the genome including the telomeric ends of chromosomes and oncogene regulatory regions. Recent studies have demonstrated that small molecules can facilitate the formation of, and stabilize, G-quadruplexes. The possible role of G-quadruplex-interactive compounds as pharmacologically important molecules is explored in this article.

Animals↗
PubMed2002

Perylene diimides with different side chains are selective in inducing different G-quadruplex DNA structures and in inhibiting telomerase.

Four N,N'-disubstituted perylene diimides, having different side chains, have been studied for their ability in inducing G-quadruplex DNA structures. We found that electrostatic interactions between ligands side chains and DNA grooves play a main role not only in the amount of G-quadruplex formed, but also in selecting its topology. Moreover, such compounds show also a different ability to inhibit telomerase. The correlation of these findings suggests the intriguing possibility that different G-quadruplex structures could differently inhibit the enzyme.

Base Sequence↗
PubMed1998

Biologically active oligodeoxyribonucleotides. Part 11: The least phosphate-modification of quadruplex-forming hexadeoxyribonucleotide TGGGAG, bearing 3-and 5-end-modification, with anti-HIV-1 activity.

We have found that a hexadeoxyribonucleotide (5'TGGGAG3', R-95288), Koizumi, M. et al. Bioorganic & Medicinal Chemistry, 1997, 5, 2235, bearing a 3,4-dibenzyloxybenzyl (3,4-DBB) group at the 5'-end and a 2-hydroxyethylphosphate at the 3'-end, has high anti-HIV-1 activity and the least cytotoxicity in vitro and in vivo. In order to synthesize more potent hexadeoxyribonucleotides, we substituted phosphodiester (P-O) bonds in the 6-mer with the least phosphorothioate (P-S), phosphoramidate (P-N), or methylphosphonate (P-Me) bonds. When more than two P-N or P-Me bonds were introduced into a 6-mer, the phosphate-modified 6-mers had weak or no anti-HIV- activity, in spite of quadruplex structure formation. However, when P-S bonds were substituted for P-O bonds, anti-HIV-1 activity of their 6-mers did not dramatically decrease, compared with compounds substituted with P-N or P-Me bonds. The results suggest that the formation of a quadruplex structure is not always sufficient for anti-HIV-1 activity of the 6-mer, and that net negative charges derived from P-O or P-S bonds in the quadruplex are important for anti-HIV-1 activity. Moreover, among various phosphate-modified ODNs, we found that the anti-HIV-1 activity of ODN PS7 with only one P-S bond was the same as that of R-95288, both having a high stability in human plasma.

Anti-HIV Agents↗
PubMed1995

Solution structures of unimolecular quadruplexes formed by oligonucleotides containing Oxytricha telomere repeats.

BACKGROUND: Oligonucleotides containing the guanine-rich telomeric sequence of Oxytricha chromosomes (dT4G4) have previously been shown to form DNA quadruplexes comprising guanine quartets stabilized by cations. Two different structures have been reported for both d(G4T4G4) (Oxy1.5) and d(G4T4G4T4G4T4G4) (Oxy3.5). RESULTS: Here we present the solution structure of a uracil- and inosine-containing derivative of Oxy3.5, d(G4TUTUG4T4G4UUTTG3I) (Oxy3.5-U4128), determined using two-dimensional 1H and 31P NMR techniques. This oligonucleotide forms a unimolecular quadruplex that is very similar to the dimeric Oxy1.5 solution structure, in that it contains a loop spanning the diagonal of an end quartet. The groove widths, strand polarities, and positions of the syn bases along the G4 tracts and within the quartets are all as reported for Oxy1.5. The first and third pyrimidine tracts form parallel loops spanning a wide groove and a narrow groove respectively. CONCLUSIONS: Both Oxy3.5 and Oxy3.5-U(4)128 form unimolecular quadruplexes in solution with a diagonal central T4 loop. These results conflict with those reported for d(G4TUTUG4TTUUG4UUTTG4) in solution, in which the central loop spans a wide groove.

Animals↗
PubMed1993

Selective localization and rotational immobilization of univalent cations on quadruplex DNA.

The quadruplex structure of the oligomer d(T2G4T) is more stable in the presence of K+ than in the presence of Na+. This enhanced stability correlates with the preferential binding of K+ to a small number of specific sites on the quadruplex. In contrast, Na+ and K+ compete on an equal footing for atmospheric binding. Both 39K+ and 23Na+ are, when specifically bound, significantly inhibited in their rotational mobility, so that the quadrupolar relaxation reflects the molecular tumbling of the oligomer, which occurs on the time scale of nanoseconds. This rotational immobilization is in distinct contrast to the high rotational mobility of atmospherically bound cations. On the other hand, all NMR-visible 39K+ in solution is in rapid exchange among all environments (free, specifically bound, and atmospherically bound) implying that the lifetime of specifically coordinated 39K+ must be significantly shorter than a millisecond. A similar conclusion holds for 23Na+. The oligomer d(T2G4T) forms two distinct Hoogsteen base-paired structures in NaCl solution, separated by a large kinetic barrier. Neither of these structures is as stable with respect to base pair opening as is the quadruplex structure formed in KCl solution. Only one of these two structures is associated with rotational immobilization of bound 23Na+.

Cations, Monovalent↗
PubMed2001

Folding of the thrombin aptamer into a G-quadruplex with Sr(2+): stability, heat, and hydration.

It has been shown that the DNA aptamer d(G(2)T(2)G(2)TGTG(2)T(2)G(2)) adopts an intramolecular G-quadruplex structure in the presence of K+. Its affinity for trombin has been associated with the inhibition of thrombin-catalyzed fibrin clot formation. In this work, we used a combination of spectroscopy, calorimetry, density, and ultrasound techniques to determine the spectral characteristics, thermodynamics, and hydration effects for the formation of G-quadruplexes with a variety of monovalent and divalent metal ions. The formation of cation-aptamer complexes is relatively fast and highly reproducible. The comparison of their CD spectra and melting profiles as a function of strand concentration shows that K+, Rb+, NH(4)+, Sr(2+), and Ba(2+) form intramolecular cation-aptamer complexes with transition temperatures above 25 degrees C. However, the cations Li+, Na+, Cs+, Mg(2+), and Ca(2+) form weaker complexes at very low temperatures. This is consistent with the observation that metal ions with ionic radii in the range 1.3-1.5 A fit well within the two G-quartets of the complex, while the other cations cannot. The comparison of thermodynamic unfolding profiles of the Sr(2+)-aptamer and K+ -aptamer complexes shows that the Sr(2+)-aptamer complex is more stable, by approximately 18 degrees C, and unfolds with a lower endothermic heat of 8.3 kcal/mol. This is in excellent agreement with the exothermic heats of -16.8 kcal/mol and -25.7 kcal/mol for the binding of Sr(2+) and K+ to the aptamer, respectively. Furthermore, volume and compressibility parameters of cation binding show hydration effects resulting mainly from two contributions: the dehydration of both cation and guanine atomic groups and water uptake upon the folding of a single-strand into a G- quadruplex structure.

Calorimetry, Differential Scanning↗
PubMed2003

G-quadruplex formation of thrombin-binding aptamer detected by electrospray ionization mass spectrometry.

Electrospray ionization mass spectrometry detected the formation of the G-quadruplex structure of the thrombin-binding aptamer, d(GGTTGGTGTGGTTGG), and established its specific interaction with metal ions. One piece of evidence that the bonding in the gas phase is via the G-quadruplex form is the enhanced binding, with respect to other metal ions, of the aptamer with Sr2+, Pb2+, Ba2+, and K+, which are of similar size. Another is the lack of specific binding with controls in which the G's are replaced with A's. The most convincing evidence is the extent of H/D exchange of the gas-phase aptamer as compared to that bound to K+ and Sr2+. The latter two complexes exchange six and nine fewer H's, indicating a significant increase in protection upon binding to the metals. Mass spectrometry will be an important tool in understanding G-quadruplexes, which are particularly important in DNA telomers.

DNA↗
PubMed2004

A PNA4 quadruplex.

A tetrameric PNA, TGGG, has been shown to form an intermolecular G-quadruplex. Nanoelectrospray mass spectrometry, combined with solution-phase H/D exchange, established formation of a specific tetramolecular complex. UV melting studies show that this complex undergoes a quadruplex melting transition. This is a novel four-stranded structure that offers the gross structural features of a DNA quadruplex, but without the negatively charged backbone.

Chemical Phenomena↗
PubMed2004

The dynamic character of the G-quadruplex element in the c-MYC promoter and modification by TMPyP4.

The nuclease hypersensitivity element III1 (NHE III1) upstream of the P1 and P2 promoters of c-MYC controls 80-90% of the transcriptional activity of this gene. The purine-rich strand in this region can form a G-quadruplex structure that is a critical part of the silencer element for this promoter. We have demonstrated that this G-quadruplex structure can form a mixture of four biologically relevant parallel-loop isomers, which upon interaction with the cationic porphyrin TMPyP4 are converted to mixed parallel/antiparallel G-quadruplex structures.

DNA↗
PubMed2004

Propeller-type parallel-stranded G-quadruplexes in the human c-myc promoter.

The nuclease-hypersensitivity element III1 in the c-myc promoter is a good anticancer target since it largely controls transcriptional activation of the important c-myc oncogene. Recently, the guanine-rich strand of this element has been shown to form an equilibrium between G-quadruplex structures built from two different sets of G-stretches; two models of intramolecular fold-back antiparallel-stranded G-quadruplexes, called "basket" and "chair" forms, were proposed. Here, we show by NMR that two sequences containing these two sets of G-stretches form intramolecular propeller-type parallel-stranded G-quadruplexes in K(+)-containing solution. The two structures involve a core of three stacked G-tetrads formed by four parallel G-stretches with all anti guanines and three double-chain-reversal loops bridging three G-tetrad layers. The central loop contains two or six residues, while the two other loops contain only one residue.

DNA↗
PubMed2006

Quadruplex-to-duplex transition of G-rich oligonucleotides probed by cationic water-soluble conjugated polyelectrolytes.

G-quartet DNA converts to duplex form in the presence of its complementary strand. This conformational change can be detected in real time by a homogeneous assay method based on the signal amplification of conjugated polyelectrolytes and the specific interaction of intercalating dyes with double-stranded DNA (dsDNA). The probe solution contains a cationic, conjugated polymer (CCP), G-quadruplex labeled with a fluorescein at the 5'-terminus (G-quadruplex-Fl), and ethidium bromide (EB). The addition of a complementary target results in the transition from G-quadruplex to duplex (dsDNA-Fl) and EB intercalation within the duplex structure. Excitation of the CCP leads to energy transfer from CCP to dsDNA-Fl (FRET-1) and then energy transfer from dsDNA-Fl to EB (FRET-2). Increasing the number of mismatched bases discourages dsDNA formation, which is detected in the assay.

Cations↗
PubMed1999

Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships.

Inhibition of the ability of the enzyme telomerase to add telomeric repeats to the end of chromosomes is a novel target for potential anticancer therapy. This paper examines the hypothesis that compounds possessing a planar aromatic chromophore inhibit telomerase via stabilization of, and binding to, a folded guanine quadruplex structure. Two series of telomerase inhibitors have been designed based on the 2,6-disubstituted amidoanthracene-9,10-dione and 3,6-disubstituted acridine chromophores in order to investigate structure-activity relationships between biological activity and substituent group size. The relative binding energies between these compounds and the folded human telomere DNA quadruplex were determined using molecular simulation methods, involving explicitly solvated structures. The results obtained are in excellent agreement with the biological activity as measured in vitro using a modified TRAP assay and in general agreement with the ranking order of binding enthalpies found in isothermal titration calorimetry studies. This broad agreement provides strong support for the hypothesis that guanine quadruplexes are the primary target for telomerase inhibitors with extended planar chromophores.

Acridines↗
PubMed2003

Structure of the parallel-stranded DNA quadruplex d(TTAGGGT)4 containing the human telomeric repeat: evidence for A-tetrad formation from NMR and molecular dynamics simulations.

The structure of the intermolecular DNA quadruplex d(TTAGGGT)4, based on the human telomeric DNA sequence d(TTAGGG), has been determined in solution by NMR and restrained molecular dynamics simultations. The core GGG region forms a highly stable quadruplex with G-tetrads likely stabilised by K+ ions bound between tetrad plains. However, we have focused on the conformation of the adenines which differ considerably in base alignment, stability and dynamics from those in previously reported structures of d(AGGGT)4 and d(TAGGGT)4. We show unambiguously that the adenines of d(TTAGGGT)4 are involved in the formation of a relatively stable A-tetrad with well-defined glycosidic torsion angles (anti), hydrogen bonding network (adenine 6-NH2-adenine N1) defined by interbase NOEs, and base stacking interactions with the neighbouring G-tetrad. All of these structural features are apparent from NOE data involving both exchangeable and non-exchangeable protons. Thus, context-dependent effects appear to play some role in dictating preferred conformation, stability and dynamics. The structure of d(TTAGGGT)4 provides us with a model system for exploiting in the design of novel telomerase inhibitors that bind to and stabilise G-quadruplex structures.

Base Sequence↗
PubMed2000

Induction of duplex to G-quadruplex transition in the c-myc promoter region by a small molecule.

A major control element of the human c-myc oncogene is the nuclease-hypersensitive purine/pyrimidine-rich sequence. This double-stranded DNA fragment, corresponding to the 27-base pair segment in the nuclease-hypersensitive element of the c-myc promoter region, forms a stable Watson-Crick double helix under physiological conditions. However, this duplex DNA can be effectively converted to G-quadruplex DNA by a small molecular weight ligand. Both intermolecular and intramolecular G-quadruplex forms can be induced by this ligand. Similar transitional changes are also observed with the duplex telomeric sequence from the Oxytricha species. These results provide additional support to the idea that G-quadruplex structures may play structural roles in vivo and also provide insight into novel methodologies for rational drug design. These structurally altered DNA elements might serve as regulatory signals in gene expression or in telomere dynamics and hence are promising targets for drug action.

Animals↗
PubMed2003

Structural isomers and binding sites of guanine-rich quadruplexes investigated by induced circular dichroism of thionin: loops and tails.

Induced circular dichroism has been used to study the binding of thionin molecule to twelve guanine-rich quadruplexes. Substituting the base in the loops and varying the length of the tails could substantial change the induced circular dichroism spectra, which allow us to distinguish structural isomers and to determine the binding sites of quadruplexes. Our results show that external stacking on the end surface of the G-quartet associated with electrostatic interaction with the loops or tails is the major binding mode of thionin with these G-quadruplexes.

Base Sequence↗
PubMed2005

Effects of a 8-oxoadenosine incorporation on quadruplex structures: thermal stabilities and structural studies.

The effects of incorporation of 8-oxoadenosine in two different truncations of human telomeric sequence forming quadruplex structures are reported. In order to characterise their structures, a combination of NMR and UV spectroscopy and computational techniques were used. Both oligonucleotides have been found to form fourfold symmetric quadruplex structures. As a tautomeric equilibrium between keto and enol forms of 8-oxoadenosine may establish in solution and intrinsic stabilities effects, such as internal H-bonds, for example, may determine the predominance of some particular tautomer, molecular modelling studies were performed on quadruplex structures containing both the tautomeric forms. Both molecules resulted to be thermally less stable than the natural.

Adenosine↗