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PubMed2005

Molecular modeling studies of a parallel stranded quadruplexes containing a 8-bromoadenosine.

Truncated sequences of human telomeric DNA can readily assemble to form parallel stranded quadruplexes containing A- and G-tetrads. The formation of an A-tetrad is highly context-dependent and the relationship between the formation of an A-tetrad and the glycosidic torsion angle of the adenosine residues implicated has not been completely clarified so far. In order to give a further insight in this issue we synthesized the modified oligomers d(ABrGGGT) and d(TABrGGGT), two different truncations of the human telomeric sequence containing a 8-bromoadenosine residue, named ABr. NMR data show that both the modified oligomers are able to perfectly fold into highly symmetric quadruplexes with all strands parallel to each other. Molecular modeling studies were performed on both [d(ABrGGGT)]4 and [d(TABrGGGT)]4, indicating that a bulky substituent, such as a bromine atom at the C8 position of adenines, can force the glycosidic bond to adopt a syn conformation, stabilizing the resulting quadruplexes.

Adenosine↗
PubMed2005

Structural studies on LNA quadruplexes.

LNAs (locked nucleic acids) are new DNA analogues with higher binding affinities toward nucleic acids than the canonical counterparts mainly due to the characteristic conformational restriction arising from the 2'-O, 4'-C methylene bridge. In light of the promising therapeutic applications and considering the advantageous characteristics of LNAs, such as their high water solubility, easy handling, and synthetic accessibility through the conventional phosphoramidite chemistry, we undertook a study concerning the capability of these nucleic acid analogues to form quadruplex structures. Particularly, we have been investigating the LNA/DNA chimeras corresponding to the well-known DNA sequences 5-GGTTGGTGTGGTTGG-3', capable of forming an unimolecular quadruplex. This article deals with the study of the sequence 5'-ggTTggTGTggTTgg-3' (upper and lower case letters represent DNA and LNA residues, respectively), which, according to CD spectroscopy, is able to fold into a quadruplex structure.

Circular Dichroism↗
PubMed1999

NMR observation of T-tetrads in a parallel stranded DNA quadruplex formed by Saccharomyces cerevisiae telomere repeats.

We report here the NMR structure of the DNA sequence d-TGGTGGC containing two repeats of Saccharomyces cerevisiae telomere DNA which is unique in that it has a single thymine in the repeat sequence and the number of Gs can vary from one to three. The structure is a novel quadruplex incor-porating T-tetrads formed by symmetrical pairing of four Ts via O4-H3 H-bonds in a plane. This is in contrast to the previous results on other telomeric sequences which contained more than one T in the repeat sequences and they were seen mostly in the flexible regions of the structures. We observed that the T4-tetrad was nicely accommodated in the center of the G-quadruplex, but it caused a small underwinding of the right handed helix. The T tetrad stacked well on the adjacent G3-tetrad, but poorly on the G5 tetrad. Likewise, T1 also formed a stable T-tetrad at the 5' end of the quadruplex. To our knowledge, this is the first report of T-tetrad formation in DNA structures. These observations are of significance from the points of view of both structural diversity and specific recognitions.

DNA, Fungal↗
PubMed2000

Structures of the potassium-saturated, 2:1, and intermediate, 1:1, forms of a quadruplex DNA.

Potassium can stabilize the formation of chair- or edge-type quadruplex DNA structures and appears to be the only naturally occurring cation that can do so. As quadruplex DNAs may be important in the structure of telomere, centromere, triplet repeat and other DNAs, information about the details of the potassium-quadruplex DNA interactions are of interest. The structures of the 1:1 and the fully saturated, 2:1, potassium-DNA complexes of d(GGTTGGTGTGGTTGG) have been determined using the combination of experimental NMR results and restrained molecular dynamics simulations. The refined structures have been used to model the interactions at the potassium binding sites. Comparison of the 1:1 and 2:1 potassium:DNA structures indicates how potassium binding can determine the folding pattern of the DNA. In each binding site potassium interacts with the carbonyl oxygens of both the loop thymine residues and the guanine residues of the adjacent quartet.

Binding Sites↗
PubMed2002

Anti-HIV-1 activity of L-DNA quadruplex.

Zintevir is a DNA 17mer that forms a quadruplex and shows strong anti-human immunodeficiency virus (HIV)-1 activity. The quadruplex formation is thought to be essential for the anti-HIV-1 activity of Zintevir. We synthesized the enantiomer of Zintevir and evaluated its structure and anti-HIV-1 activity. The results showed that the enantiomer has anti-HIV-1 activity comparable to that of Zintevir although it forms the mirror image quadruplex structure of Zintevir.

Anti-HIV Agents↗
PubMed1995

Solution structure of the Na+ form of the dimeric guanine quadruplex [d(G3T4G3)]2.

The solution structure of the DNA quadruplex formed by the association of two strands of the DNA oligonucleotide, d(G3T4G3), in NaCl solution has been determined by 1H two-dimensional NMR techniques, full relaxation matrix calculations and restrained molecular dynamics. The refined structure incorporates the sequences 5'-G1sG2AG3AT4AT5AT6AT7AG8sG9AG10A-3' and 5'-G11sG12AG13AT14AT15AT16AT17AG18sG19sG20A-3' (where S and A denote syn and anti, respectively) in a three-quartet, diagonal-looped structure that we [Strahan, G. D., Shafer, R. H. & Keniry, M. A. (1994) Nucleic Acids Res. 22, 5447-5455] and others [Smith, F. W., Lau, F. W. & Feigon, J. (1994) Proc. Natl. Acad. Sci. USA 91, 10546-10550] have described. The loop structure is compact and incorporates many of the features found in duplex hairpin loops including base stacking, intraloop hydrogen bonding and extensive van der Waals' interactions. The first and third loop thymines stack over the outermost G-quartet and are also associated by hydrogen bonding. The second and the fourth loop thymines fold inwards in order to enhance van der Waals' interactions. The unexpected sequential syn-syn deoxyguanosines in the quadruplex stem appear to be a direct consequence of the way DNA oligonucleotides fold and the subsequent search for the most stable loop structure. The implications of loop sequence and length on the structure of quadruplexes are discussed.

Guanine↗
PubMed2006

G-quadruplexes induce apoptosis in tumor cells.

Several G-rich oligodeoxynucleotides (ODNs), which are capable of forming G-quadruplexes, have been shown to exhibit antiproliferative activity against tumor cell lines and antitumor activity in nude mice carrying prostate and breast tumor xenografts. However, the molecular basis for their antitumor activity remains unclear. In the current study, we showed that a variety of telomeric G-tail oligodeoxynucleotides (TG-ODNs) exhibited antiproliferative activity against many tumor cells in culture. Systematic mutational analysis of the TG-ODNs suggests that the antiproliferative activity depends on the G-quadruplex conformation of these TG-ODNs. TG-ODNs were also shown to induce poly(ADP-ribose) polymerase-1 cleavage, phosphatidylserine flipping, and caspase activation, indicative of induction of apoptosis. TG-ODN-induced apoptosis was largely ataxia telangiectasia mutated (ATM) dependent. Furthermore, TG-ODN-induced apoptosis was inhibited by the c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125. Indeed, TG-ODNs were shown to activate the JNK pathway in an ATM-dependent manner as evidenced by elevated phosphorylation of JNK and c-Jun. Interestingly, a number of G-quadruplex ODNs (GQ-ODN) derived from nontelomeric sequences also induced ATM/JNK-dependent apoptosis, suggesting a possible common mechanism of tumor cell killing by GQ-ODNs.

Animals↗
PubMed2001

G-quadruplex DNA structures--variations on a theme.

To be functional, nucleic acids need to adopt particular three-dimensional structures. For a long time DNA was regarded as a rigid and passive molecule with the sole purpose to store genetic information, but experimental data has now accumulated that indicates the full dynamic repertoire of this macromolecule. During the last decade, four-stranded DNA structures known as G-quadruplexes, or DNA tetraplexes, have emerged as a three-dimensional structure of special interest. Motifs for the formation of G-quadruplex DNA structures are widely dispersed in eukaryotic genomes, and are abundant in regions of biological significance, for example, at telomeres, in the promoters of many important genes, and at recombination hotspots, to name but a few in man. Here I explore the plethora of G-quadruplex DNA structures, and discuss their possible biological functions as well as the proteins that interact with them.

Animals↗
PubMed2003

The design of G-quadruplex ligands as telomerase inhibitors.

Guanine-rich repetitive DNA sequences are of particular importance at the ends of chromosomes, where they are associated with a number of proteins to form telomeres. Their function is in large part to protect chromosomal ends from unwanted degradation and chromosomal fusions, although in normal somatic cells telomeres progressively shorten, eventually becoming non-proliferating and consequently these cells have a finite lifetime. By contrast tumour cell telomeres are maintained in length so that tumour cells are effectively immortalised. The reverse transcriptase enzyme telomerase is activated in over 80% of tumour cells, and it undertakes the synthesis of further telomeric DNA repeats, so directly maintaining telomeres. The inhibition of telomerase leads to the senescence and eventual apoptosis of tumour cells, and thus telomerase is an attractive target for selective chemotherapy. This review describes an approach to the inhibition of telomerase that involves the folding of telomeric DNA into a four-stranded quadruplex structure, held together by Hoogsteen hydrogen-bonded arrays of guanine bases. The formation of a quadruplex structure at the 3' end of telomeric DNA effectively hinders telomerase from adding further repeats. A number of small-molecule ligands are described that stabilise quadruplex formation, and which result in telomerase inhibition. Implications for anti-tumour therapy with such molecules are discussed, and the particular challenges and problems discussed.

Computer Simulation↗
PubMedDate not supplied

[Four-stranded complexes of oligonucleotides--quadruplexes].

The review presents analysis of the experimental, model and calculation studies concerned with the formation of the four-stranded helices of the natural and synthetic oligonucleotides. Guanine-rich oligonucleotides form stable four-stranded helices. Structures of such complexes were investigated by means of X-rays and spectrographic methods. These works have been reviewed in the first part. There are three possible variants of noncanonical structures formed by oligoguanylic acids. Two of them--four-stranded helices differed by the mutual direction of the sugar-phosphate chains. The third one is the two-stranded hairpin. Regulation of the number of cellular processes by means of the structural conversions between these three forms of guanine-rich motifs are investigated in articles reviewed in the second part. These works are concerned with the structural organization and functions of telomers, and on the other hand with the possible role of quadruplexes in self-recognition processes of the four homologous chromatids during meiosis and the following recombination. The third part of the review considers quadruplexes with an arbitrary sequence. In general there are model works inspired by investigations of recombination and replication processes. Experimental data concerned with the formation of quadruplex structures from two decamer Watson-Crick base paired duplexes oligo(dA).oligo(dT) are also presented.

Nucleic Acid Conformation↗
PubMedDate not supplied

Dimer linkage structure in retroviruses: models that include both duplex and quadruplex domains.

Genome of all known retroviruses consists of two identical molecules of RNA, which are non-covalently linked. The most stable contact site between two RNA molecules is located near their 5' ends. The molecular interactions in the dimer linkage structure (DLS) in mature virions are currently unknown. Recently we suggested that the dimer linkage structure in human immunodeficiency virus 1 (HIV-1) contains both duplex and quadruplex domains and proposed a model of DLS in HIV-1Mal (Central African virus). In this paper we showed that similar models can be also built for HIV- 1Lai, a representative of the North-American and European viruses. One of the double-stranded domains in the model structures represents either an extended duplex formed by different pathways (through base pair melting and subsequent reannealing or by a recombination mechanism) or kissing loop complex. The quadruplexes contain both G- and mixed tetrads, for example, G.C.G.C or A.U.A.U. Phylogenetic analysis of 350 isolates from NCBI database showed that similar models of DLS are predictable practically for all HIV-1 isolates surveyed. A model of dimer linkage structure in Moloney murine sarcoma virus (MuSV) is also presented. The structure includes a duplex formed by the palindromic sequences and several quadruplexes.

Animals↗
PubMed1995

Antibodies specific for the DNA quadruplex [d(CGC G4 GCG)4] isolated from autoimmune mice.

An autoantibody specific for a DNA quadruplex structure has been isolated and cloned from three-month-old autoimmune "viable motheaten" mice. This antibody (mev-alpha Q1) has been tested extensively in vitro and found to bind specifically and preferentially to the parallel-stranded quadruplex structure formed by the oligonucleotide d(CGC G4 GCG). The anti-quadruplex antibody does not show specific affinity for single-, double-, or triple-stranded oligonuclotides of similar CG-rich sequence motifs.

Animals↗
PubMed2006

Synthesis and characterization of DNA quadruplexes containing T-tetrads formed by bunch-oligonucleotides.

The solid phase syntheses of the bunch oligonucleotides and based on the sequences of the natural oligodeoxynucleotides (ODNs) d(TG2TG2C) and d(CG2TG2T), respectively, attached to a non-nucleotidic tetrabranched linker, are reported. Bunch-ODNs and were shown to form more stable monomolecular parallel G-quadruplexes and when compared with their tetramolecular counterparts [d(TG2TG2C)]4 and [d(CG2TG2T)]4, respectively. The structure and stability of all the synthesized complexes have been investigated by circular dichroism (CD), CD thermal denaturation experiments, and 1H-NMR (nuclear magnetic resonance) experiments at variable temperatures. Particularly, the spectroscopic data confirmed that 1 adopts a T-tetrad containing parallel-stranded quadruplex structure as in the tetramolecular complex.

Circular Dichroism↗
PubMed2005

Quadruplex-duplex competition in the nuclease hypersensitive element of human c-myc promoter: C to T mutation in C-rich strand enhances duplex association.

The nuclease hypersensitive element NHE III(I) is an important anti-cancer target as the transcription of oncogene c-myc is largely regulated by it. It has been postulated that regulatory control is mediated by G-quadruplex formation in the NHE anti-sense strand through a competition between the duplex and the quadruplex states. A mutation in the NHE has been implicated in cancer. In this study, the reported mutation has been characterized vis-a-vis the kinetics of i-tetraplex formation (in the sense strand) and its effect on duplex formation. We found that i-tetraplex formation was destabilized by approximately 1.4 kcal/mol (DeltaDeltaG at 20 degrees C, pH 5.8). Observed hysteresis allowed us to analyze the kinetics of folding for the mutant (M3). Though we observed higher association (DeltaEon approximately -23.4 kcal/mol) and dissociation (DeltaEoff approximately 22.1 kcal/mol) activation energies (at pH 5.3) for the wild-type (P1) tetraplex folding, the kinetics of folding and unfolding for M3 was somewhat faster at pH 5.3 and 5.8. Interestingly, Surface plasmon resonance (BIAcore) analysis of hybridization at pH 6.6 indicated a higher association constant for M3 (approximately 22.5 x 10(4)M(-1)s(-1)) than P1 (approximately 3.2 x 10(4)M(-1)s(-1)). The equilibrium dissociation constants also indicated favorable duplex association for M3 (approximately 22.2 and approximately 190.6 nM for M3 and P1, respectively). We envisage that the increased affinity for the duplex state due to the mutation could play a functional role in the aberrant regulation of c-myc.

Base Pairing↗
PubMed2006

I-motif and quadruplex-based device that can control a protein release or bind and release small molecule to influence biological processes.

To expand the function of DNA machines, we constructed a non-DNA-fuel machine based on the G-quadruplex and i-motif structures within the telomere DNA sequence. Depending on the binding or non-binding of the specified form, the DNA machine is able to bind or release the telomere-binding protein TRF 1, and to release small quadruplex-binding molecules to impede progress of the polymerase. This DNA machine, driven by pH change, does not accumulate duplex DNA waste products to poison the system. These new functions undertaken by structured nucleic acids open many opportunities to create and expand the further functions and use of DNA and RNA.

Circular Dichroism↗
PubMed2004

Aggregation and G-quadruplex DNA-binding study of 6a,12a-diazadibenzo-[a,g]fluorenylium derivative.

The aggregation and DNA binding behavior of a new G-quadruplex selective ligand, 6a,12a-diazadibenzo-[a,g]fluorenylium derivative, was studied by UV-vis absorption and fluorescence spectroscopy. The formation of ligand aggregates with different spectral characteristics was observed at low and high concentration of NaCl, respectively. The ligand binds to G-quadruplex with much higher affinity than to single- and double-stranded DNA.

Aza Compounds↗
PubMed2003

Formation pathways of a guanine-quadruplex DNA revealed by molecular dynamics and thermodynamic analysis of the substates.

The formation of a cation-stabilized guanine quadruplex (G-DNA) stem is an exceptionally slow process involving complex kinetics that has not yet been characterized at atomic resolution. Here, we investigate the formation of a parallel stranded G-DNA stem consisting of four strands of d(GGGG) using molecular dynamics simulations with explicit inclusion of counterions and solvent. Due to the limitations imposed by the nanosecond timescale of the simulations, rather than watching for the spontaneous formation of G-DNA, our approach probes the stability of possible supramolecular intermediates (including two-, three-, and four-stranded assemblies with out-of-register base pairing between guanines) on the formation pathway. The simulations suggest that "cross-like" two-stranded assemblies may serve as nucleation centers in the initial formation of parallel stranded G-DNA quadruplexes, proceeding through a series of rearrangements involving trapping of cations, association of additional strands, and progressive slippage of strands toward the full stem. To supplement the analysis, approximate free energies of the models are obtained with explicit consideration of the integral cations. The approach applied here serves as a prototype for qualitatively investigating other G-DNA molecules using molecular dynamics simulation and free-energy analysis.

Cations↗