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PubMed1997

Interaction of a G-DNA quadruplex with mono- and divalent cations. A force field calculation.

The formation and stability of four-stranded DNA in solution is specifically dependent on the type of cations present. The interaction potential of a model quadruplex structure with different mono- and divalent ions was determined by force field calculations. Though the electrostatic contribution to the total energy is mainly responsible for the stabilisation of the cations within the quadruplex channel, it is the van der Waals interaction at short distances that determines the specific characteristics of the different cations. An explicit consideration of the solvent indicates that the position of water molecules in close proximity to the DNA channel have a strong influence on the form of the potential, and hence on the capability of the cations for leaving and re-entering the cavity. The effect of cation size, as expressed through their Lennard-Jones parameters, is discussed.

Journal Article↗
PubMed2000

2'-Deoxy-8-(propyn-1-yl)adenosine-containing oligonucleotides: effects on stability of duplex and quadruplex structures.

2'-Deoxy-8-(propyn-1-yl)adenosine has been incorporated in synthetic oligodeoxyribonucleotides and its influence on thermal stability of duplex and quadruplex structures investigated by UV, CD and 1H NMR. The obtained results seem to indicate that the presence of the modified base negatively affects the stability of double stranded DNA whereas remarkably increases the stability of parallel quadruplex structures.

Adenosine↗
PubMedDate not supplied

Directing quadruplex-stabilizing drugs to the telomere: synthesis and properties of acridine-oligonucleotide conjugates.

Conjugates containing quadruplex-stabilizing acridines linked to oligonucleotides that are complementary to the G-rich human telomere sequence were synthesized. Acylation of 3,6-diaminoacridine followed by two Michael reactions provided derivatives suitable for conjugation, which were coupled to resin-linked amine-modified oligonucleotides by activating the carboxyl group with pentafluorophenyl 4-nitrobenzenesulfonate. After deprotection with aqueous ammonia at room temperature, conjugates incorporating different acridines, linkers, and oligonucleotide sequences were obtained. These were tested for their ability to stabilize intramolecular DNA quadruplexes that are based on the human telomeric repeat sequence (GGGTTA)(n).

Acridines↗
PubMed1993

Strand orientation in the DNA quadruplex formed from the Oxytricha telomere repeat oligonucleotide d(G4T4G4) in solution.

The structure formed from the DNA oligonucleotide d(G4T4G4) (Oxy-1.5), which contains the Oxytricha telomere repeat T4G4, has been investigated by two-dimensional 1H and 31P NMR spectroscopy. Sequence-specific assignments have been obtained for the 1H and 31P resonances, using a combination of methods including comparisons to the inosine- and uracil-containing derivatives d(G4T4G3I) and d(G4UT3G4). The oligonucleotide forms a symmetrical bimolecular G-quadruplex with four G-quartets and thymine loops at opposite ends of the G-quartets. Guanines are alternatively syn and anti along each "strand" and all of the thymines are anti. The thymines loop diagonally across the G-quartet, resulting in a structure in which adjacent strands are alternately parallel and antiparallel and the glycosidic torsion angles are syn-syn-anti-anti around each G-quartet. There are three different types of grooves, a wide, a narrow, and two medium grooves. A diagonally looped quadruplex is formed in the presence of both Na+ and K+ counterions. The model structure of Oxy-1.5 is compared to the recently published crystal structure of Oxy-1.5 (Kang et al., 1992), which contains many of the same features as those found in solution but differs in that the thymines loop across an edge of the G-quartet.

Animals↗
PubMed2002

The sodium ions inside a lipophilic G-quadruplex channel as probed by solid-state (23)Na NMR.

We report solid-state 23Na NMR and X-ray crystallographic results for a self-assembled G-quadruplex channel formed by a guanine nucleoside, 5'-tert-butyl-dimethylsilyl-2',3'-O-isopropylidene guanosine (G 1). The study provides an unambiguous 23Na NMR identification for the Na+ ions inside a lipophilic G-quadruplex channel. The crystalline nature of the sample yields a remarkably high resolution in the 23Na multiple-quantum magic-angle spinning (MQMAS) spectrum, making it possible to extract very accurate 23Na NMR parameters for each of the three crystallographically distinct Na sites. The observation of a single Na+ ion from a 9-kDa system demonstrates the potential of solid-state 23Na NMR as a complementary technique to X-ray for detecting Na+ ions in biological structures.

Guanine↗
PubMed2006

PNA-DNA duplexes, triplexes, and quadruplexes are stabilized with trans-cyclopentane units.

Peptide nucleic acids (PNAs) are non-natural nucleic acid mimics that bind to complementary DNA and RNA with high affinity and selectivity. PNA can bind to nucleic acids in a number of different ways. Currently, the formation of PNA-oligonucleotide duplex, triplex, and quadruplex structures have been reported. PNAs have been used in numerous biomedicial applications, but there are few strategies to predictably improve the binding properties of PNAs by backbone modification. We have been studying the benefits of incorporating (S,S)-trans-cyclopentane diamine units (tcyp) into the PNA backbone. In this Communication, we report the improvement in stability associated with tcyp incorporation into PNA-DNA duplexes, triplexes, and quadruplexes. The broad utility of this modification across multiple types of PNA structures is unique and should prove useful in the development of applications that rely on PNA.

Cyclopentanes↗
PubMed1992

Quadruplex structure of Oxytricha telomeric DNA oligonucleotides.

The telomeres of most eukaryotes contain a repeating G-rich sequence with the consensus d(T/A)1-4G1-8, of which 12-16 bases form a 3' single-strand overhang beyond the telomeric duplex. It has been proposed that these G-rich oligonucleotides associate to form four-stranded structures from one, two or four individual strands and that these structures may be relevant in vivo. The proposed structures contain Hoogsteen base-paired G-quartets, precedent for which has been in the literature for many years. Here we use 1H NMR spectroscopy to study the conformations of the DNA oligonucleotides d(G4T4G4) (Oxy-1.5) and d(G4T4G4T4G4T4G4) (Oxy-3.5) which contain the Oxytricha telomere repeat (T4G4). We find that these molecules fold to form a symmetrical bimolecular and an intramolecular quadruplex, respectively. Both structures have four G-quartets formed from nucleotides that are alternately syn and anti along each strand. This arrangement differs from earlier models in which the strands are alternately all syn or all anti. The T4 loops in Oxy-1.5 are on opposite ends of the quadruplex and loop diagonally across the G-quartet, resulting in adjacent strands being alternately parallel and antiparallel.

Animals↗
PubMed2005

Apoptosis related to telomere instability and cell cycle alterations in human glioma cells treated by new highly selective G-quadruplex ligands.

Telomerase represents a relevant target for cancer therapy. Molecules able to stabilize the G-quadruplex (G4), a structure adopted by the 3'-overhang of telomeres, are thought to inhibit telomerase by blocking its access to telomeres. We investigated the cellular effects of four new 2,6-pyridine-dicarboxamide derivatives displaying strong selectivity for G4 structures and strong inhibition of telomerase in in vitro assays. These compounds inhibited cell proliferation at very low concentrations and then induced a massive apoptosis within a few days in a dose-dependent manner in cultures of three telomerase-positive glioma cell lines, T98G, CB193 and U118-MG. They had also antiproliferative effects in SAOS-2, a cell line in which telomere maintenance involves an alternative lengthening of telomeres (ALT) mechanism. We show that apoptosis was preceded by multiple alterations of the cell cycle: activation of S-phase checkpoints, dramatic increase of metaphase duration and cytokinesis defects. These effects were not associated with telomere shortening, but they were directly related to telomere instability involving telomere end fusion and anaphase bridge formation. Pyridine-based G-quadruplex ligands are therefore promising agents for the treatment of various tumors including malignant gliomas.

Apoptosis↗
PubMed2006

G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3' telomeric overhang in cancer cells.

Inhibition of telomerase activity by telomerase inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the telomerase inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 3' single-stranded telomeric overhangs (G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal fibroblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional telomerase inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.

Anaphase↗
PubMed2006

Synthesis and G-quadruplex binding studies of new 4-N-methylpyridinium porphyrins.

A series of cationic porphyrins carrying 1-3 meso-N-pyridinium groups has been synthesised, and their binding to G-quadruplex DNA has been explored by surface plasmon resonance (SPR) and circular dichroism spectroscopy. Two trans substituents appear to be sufficient for tight binding; preferential binding to the anti-parallel intramolecular human telomeric DNA was observed for the A2trans and A3 porphyrins. The A2trans is able to induce the formation of an anti-parallel G-quadruplex in a K+ free solution, mimicking the effect of a molecular chaperone.

Circular Dichroism↗
PubMed2001

DNA quadruplexes and dynamical genetics.

In a recent paper, we have put forward the hypothesis that there exist smart purposive mechanisms - tandem repeat length managers - which regulate the length of some tandem repeat, or cause rearrangements, and are almost always driven by some variable number tandem repeat. We have called the framework in which such mechanisms act 'dynamical genetics'. The purpose of this paper is to contribute to lay the foundations of a molecular study of the above mechanisms, by proposing a hypothesis, based on various kinds of supporting evidence and plausibility arguments, about the special importance of DNA quadruplexes for dynamical genetics, and by considering the involved enzymes. This hypothesis states that a tandem repeat length manager acts almost always by monitoring a DNA tract that has the characteristics of being a variable number tandem repeat and/or forming a DNA quadruplex, and that it is almost always driven by at least one of them.

Aging↗
PubMed2003

Studies on the structure and dynamics of the human telomeric G quadruplex by single-molecule fluorescence resonance energy transfer.

We have investigated the structure and unfolding kinetics of the human telomeric intramolecular G quadruplex by using single-molecule fluorescence resonance energy transfer. An exploration of conformational heterogeneity revealed two stable folded conformations, in both sodium- and potassium-containing buffers, with small differences between their enthalpies and entropies. Both folded conformations can be opened by the addition of a 21-base complementary DNA oligonucleotide. The unfolding of both substates occurs at the same rate, which showed dependence on the monovalent metal cation present. Temperature-dependence studies in 100 mM KCl gave an apparent activation enthalpy and entropy of 6.4 +/- 0.4 kcal.mol-1 and -52.3 +/- 1.4 cal.mol-1.K-1, respectively, indicating that the unfolding is entropically driven and can occur easily. In contrast, in 100 mM NaCl the respective values are 14.9 +/- 0.2 kcal.mol-1 and -23.0 +/- 0.8 cal.mol-1.K-1, suggesting a more significant enthalpic barrier. Molecular modeling suggests that the two species are likely to be the parallel and antiparallel quadruplex structures. The unfolding free energy barrier is estimated to be between 3 and 15 kBT based on Kramers' theory. We conclude that under near-physiological conditions these structures coexist and can interconvert on a minute time scale.

Base Composition↗
PubMed1994

d(G3T4G3) forms an asymmetric diagonally looped dimeric quadruplex with guanosine 5'-syn-syn-anti and 5'-syn-anti-anti N-glycosidic conformations.

The structure formed by the DNA oligonucleotide d(G3T4G3) has been studied by one- and two-dimensional 1H NMR spectroscopy. In NaCl solution, d(G3T4G3), like d(G4T4G4) (Oxy-1.5), forms a dimeric quadruplex with the thymines in loops across the diagonal of the end quartets. Unlike Oxy-1.5, the dimer is not symmetric, and both monomer strands are observed in NMR spectra. Three quartets are formed from the GGG tracts. Glycosidic conformations of the guanines are 5'-syn-syn-anti-(loop)-syn-anti-anti in one strand and 5'-syn-anti-anti-(loop)-syn-syn-anti in the other strand. Thus, the stacking of the quartets (tail-to-tail, head-to-tail) is unlike all previously described fold-back (tail-to-tail, head-to-head) and parallel-stranded (head-to-tail, head-to-tail) quadruplexes.

Base Sequence↗
PubMed1997

Purification and characterization of qTBP42, a new single-stranded and quadruplex telomeric DNA-binding protein from rat hepatocytes.

Telomeres of vertebrate chromosomes terminate with a short 5'-d(TTAGGG)-3' single-stranded overhang that can form in vitro tetrahelical structures. Here we describe a new protein from rat hepatocyte nuclei designated quadruplex telomere-binding protein 42 (qTBP42) that tightly binds 5'-d(TTAGGG)n-3' and 5'-d(CCCTAA)n-3' single-stranded and tetraplex forms of 5'd(TTAGGG)n-3'. The thermostable qTBP42 was isolated from boiled nuclear extracts and purified to near homogeneity by successive steps of column chromatography on DEAE-cellulose, phosphocellulose, and phenyl-Sepharose. A subunit molecular size of 42.0 +/- 2.0 kDa was determined for qTBP42 by Southwestern blotting and SDS-polyacrylamide gel electrophoresis of the protein and its UV cross-linked complex with labeled telomeric DNA. A native size of 53. 5 +/- 0.9 kDa, estimated by Superdex copyright 200 gel filtration, suggests that qTBP42 is a monomeric protein. Sequences of five tryptic peptides of qTBP42 contained motifs shared by a mammalian CArG box-binding protein, hnRNP A/B, hnRNP C, and a human single-stranded telomeric DNA-binding protein. Complexes of qTBP42 with each complementary strand of telomeric DNA and with quadruplex forms of the guanine-rich strand had 3.7-14.6 nM dissociation constants, Kd, whereas complexes with double-stranded telomeric DNA had up to 100-fold higher Kd values. By associating with tetraplex and single-stranded telomeric DNA, qTBP42 increased their heat stability and resistance to digestion by micrococcal nuclease.

Amino Acid Sequence↗
PubMed1996

DNA quadruplexes assembled by simple peptide: effects of DNA homology and peptide removal.

Formation of heterologous (calf thymus dsDNA) and homologous (linearized pBR322 plasmid dsDNA) quadruplexes upon binding with the simple aliphatic tripeptide derivative (L-Val)3-N2H2-DNS.CF3COOH-DHTV) was examined by fluorimetry, flow linear (LD), circular dichroism (CD), and electron microscopy (EM). The morphology of the rod-like compact particles formed due to the association of dsDNA segments proved to be the same for both DNAs, whereas the stability of the compact DNA structure upon tripeptide removal from the complex with DNA differed substantially for homologous versus non-homologous dsDNA used. The increase in NaCl concentration in the solution up to 30 mM removes the peptide from both types of the complexes completely. At the same time at 20 mM NaCl calf thymus DNA quadruplexes readily dissociate, whereas the structures formed by plasmid DNA retain their morphology in the solution containing NaCl with concentrations up to 40 mM and are only partially disrupted at even higher NaCl concentration. These results provide an analogy between trivaline-DNA model complexes and RecA-DNA binding.

Animals↗
PubMed1999

Monte Carlo simulation of radiolytic attack to 5'-d[T4G4]4 sequence in a unimolecular quadruplex.

PURPOSE: To extend to a quadruplex the stochastic model of radiolytic attack previously applied to a quasi-random duplex DNA. MATERIALS AND METHODS: The quadruplex structure is obtained from the PDB databank (first structure from 201D entry). The probabilities of OH* radical attack at all sugar and base reaction sites are calculated using a stochastic model based on the Monte Carlo method. RESULTS: Good agreement between the calculated and experimental frank strand break (FSB) probabilities is obtained using the relative efficiencies of conversion of the C4' and C5'-centred radicals into FSB determined for the quasi-random duplex (2.8:1 respectively). Efficiencies of base radicals-to-alkali-revealed breaks (ARB) conversion are determined by fitting the calculated probabilities of base attack to the previously reported experimental probabilities for ARB. The efficiency of conversion of thymine radical into an ARB is 3.4+/-0.7 times higher than for guanine radical. CONCLUSIONS: This paper supports the calculation method and allows evaluation of the relative efficiencies of thymine and guanine radicals-to-ARB conversion.

Base Sequence↗
PubMedDate not supplied

1H-NMR study of the quadruplex [d(TGGGT)]4 containing a modified thymine.

A NMR structural study of quadruplex [d(TGGGT)]4 containing a modified thymine is reported. The three dimensional structure of the complex is very similar to those of other parallel stranded quadruplexes. The modified thymines (T*) are able, at least in the minimised structures, to form a tetrad containing extra H-bonds through the hydroxyl groups. Nevertheless, in this new tetrad the modified thymines are slightly open towards the solvent respect to the unmodified T-tetrad.

Base Sequence↗