Structure of two intramolecular G-quadruplexes formed by natural human telomere sequences in K + solution †

Phan, Anh Tuân; Kuryavyi, Vitaly; Luu, Kim Ngoc; Patel, Dinshaw J.

doi:10.1093/nar/gkm706

Cited by 494 publications

(648 citation statements)

References 58 publications

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“…In 2002, a crystal structure of the parallel-stranded G-quadruplex was reported using a 22-nt human telomeric sequence in the presence of K + [47]. Recent results have shown that hybrid-type intramolecular Gquadruplexes ( Figure 2A) appear to be the predominant conformation formed in human telomeric sequences in K + solution [48][49][50][51][52][53][54][55]. The hybrid-type structures are distinct from the Na + -structure in solution ( Figure 2B) and the crystal structure in the presence of K + ( Figure 2C).…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of human telomeric quadruplex structures

2008

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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.

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Section: Introductionmentioning

confidence: 99%

Polymorphism of human telomeric quadruplex structures

2008

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“…In contrast, NMR-based studies in KCl solution show that the same sequence folds predominantly to the hybrid-1 and hybrid-2 structures (Fig. 1A) (5)(6)(7)(8). Characteristics of this structure are an antiparallel strand orientation with a 3+1 core of syn and anti G nucleotides yielding three tetrads.…”

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confidence: 95%

Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity

Fleming

Middleton

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Human telomeric DNA consists of tandem repeats of the sequence 5′-TTAGGG-3′ that can fold into various G-quadruplexes, including the hybrid, basket, and propeller folds. In this report, we demonstrate use of the α-hemolysin ion channel to analyze these subtle topological changes at a nanometer scale by providing structuredependent electrical signatures through DNA-protein interactions. Whereas the dimensions of hybrid and basket folds allowed them to enter the protein vestibule, the propeller fold exceeds the size of the latch region, producing only brief collisions. After attaching a 25-mer poly-2′-deoxyadenosine extension to these structures, unraveling kinetics also were evaluated. Both the locations where the unfolding processes occur and the molecular shapes of the G-quadruplexes play important roles in determining their unfolding profiles. These results provide insights into the application of α-hemolysin as a molecular sieve to differentiate nanostructures as well as the potential technical hurdles DNA secondary structures may present to nanopore technology.α-hemolysin nanopore | single-molecule detection N ucleic acids can fold into a myriad of secondary structures that depend on the primary sequence as well as the physical conditions in which the structures are prepared and characterized. One prime example of a multistructural sequence is human telomeric DNA comprising the repeat sequence 5′-TTAGGG-3′. This guanine-rich single-stranded sequence is known to fold into highly ordered nanostructures in the form of G-quadruplexes that feature the coordination of two alkali cations to three layers of G-tetrads formed by Hoogsteen hydrogen-bonded assemblies of four guanine bases ( Fig. 1A) (1, 2). G-quadruplexes provide a fascinating case in which the cation and physical context play critical roles in defining the overall structural topology as well as the stability of the fold. Guanine-rich sequences also are known to present challenges to PCR amplification and sequencingby-synthesis methods that require processive analysis of singlestranded DNA (ssDNA) because of the high thermodynamic stability of these folded structures.The following studies highlight the cation and contextdependent conditions in which the topology of the natural human telomere sequence 5′-TAGGG(TTAGGG) 3 TT-3′ is affected. In NaCl solution, NMR studies revealed a structure referred to as the basket fold (Fig. 1A) (4). Key features of this structure include an antiparallel strand arrangement with alternating syn and anti orientations of the guanosine glycosidic bonds and three tetrads linked by two edgewise loops and one diagonal loop. In contrast, NMR-based studies in KCl solution show that the same sequence folds predominantly to the hybrid-1 and hybrid-2 structures (Fig. 1A) (5-8). Characteristics of this structure are an antiparallel strand orientation with a 3+1 core of syn and anti G nucleotides yielding three tetrads. The loop topology of the hybrid fold consists of a double-chain reversal loop and two edgewise loops, in which hybr...

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“…Of particular interest recently are the conformations available to G-rich DNAs which are designated as G-quadruplexes. DNA sequences that have islands of G 2-4 separated by 1 to 4 A and/or T bases can form a rich library of secondary structures with different molecularities, strand orientations, and guanine base conformation (i.e., syn or anti) [3][4][5][6][7][8][9][10][11][12][13][14]. The conformations and their stabilities are highly dependent upon the sequence context and buffer conditions [15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…A model was presented for the quadruplex to random coil transition, via formation of an unknown intramolecular intermediate, with exclusion of K + during each transition. Review of the literature reveals that different investigators have used slight variations of the sequence (TTAGGG) 4 for their investigations and have drawn conclusions based upon their data [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. We recently reported however that changing just one base in just one loop of the folded quadruplex influences both conformation and stability [20].…”

Section: Introductionmentioning

confidence: 99%

The Human Telomere Sequence, (TTAGGG)4, in the Absence and Presence of Cosolutes: A Spectroscopic Investigation

Sharma

Sheardy

2014

Molecules

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Abstract:Historically, biophysical studies of nucleic acids have been carried out under near ideal conditions, i.e., low buffer concentration (e.g., 10 mM phosphate), pH 7, low ionic strength (e.g., 100 mM) and, for optical studies, low concentrations of DNA (e.g., 1 × 10 −6 M). Although valuable structural and thermodynamic data have come out of these studies, the conditions, for the most, part, are inadequate to simulate realistic cellular conditions. The increasing interest in studying biomolecules under more cellular-like conditions prompted us to investigate the effect of osmotic stress on the structural and thermodynamic properties of DNA oligomers containing the human telomere sequence (TTAGGG). Here, we report the characterization of (TTAGGG) 4 in potassium phosphate buffer with increasing percent PEG (polyethylene glycol) or acetonitrile. In general, the presence of these cosolutes induces a conformational change from a unimolecular hybrid structure to a multimolecular parallel stranded structure. Hence, the structural change is accompanied with a change in the molecularity of quadruplex formation.

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Structure of two intramolecular G-quadruplexes formed by natural human telomere sequences in K + solution †

Cited by 494 publications

References 58 publications

Polymorphism of human telomeric quadruplex structures

Polymorphism of human telomeric quadruplex structures

Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity

The Human Telomere Sequence, (TTAGGG)4, in the Absence and Presence of Cosolutes: A Spectroscopic Investigation

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