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Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers.

ABSTRACT: Previously, it has been reported that human telomeric DNA sequences could adopt in different experimental conditions four different intramolecular G-quadruplexes each involving three G-tetrad layers, namely, Na(+) solution antiparallel-stranded basket form, K(+) crystal parallel-stranded propeller form, K(+) solution (3 + 1) Form 1, and K(+) solution (3 + 1) Form 2. Here we present a new intramolecular G-quadruplex adopted by a four-repeat human telomeric sequence in K(+) solution (Form 3). This structure is a basket-type G-quadruplex with only two G-tetrad layers: loops are successively edgewise, diagonal, and edgewise; glycosidic conformations of guanines are syn x syn x anti x anti around each tetrad. Each strand of the core has both a parallel and an antiparallel adjacent strands; there are one narrow, one wide, and two medium grooves. Despite the presence of only two G-tetrads in the core, this structure is more stable than the three-G-tetrad intramolecular G-quadruplexes previously observed for human telomeric sequences in K(+) solution. Detailed structural elucidation of Form 3 revealed extensive base pairing and stacking in the loops capping both ends of the G-tetrad core, which might explain the high stability of the structure. This novel structure highlights the conformational heterogeneity of human telomeric DNA. It establishes a new folding principle for G-quadruplexes and suggests new loop sequences and structures for targeting in human telomeric DNA.

SUBMITTER: Lim KW

PROVIDER: S-EPMC2662591 | biostudies-other | 2009 Apr

REPOSITORIES: biostudies-other

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Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers.

Lim Kah Wai KW Amrane Samir S Bouaziz Serge S Xu Weixin W Mu Yuguang Y Patel Dinshaw J DJ Luu Kim Ngoc KN Phan Anh Tuân AT

Journal of the American Chemical Society 20090401 12

Previously, it has been reported that human telomeric DNA sequences could adopt in different experimental conditions four different intramolecular G-quadruplexes each involving three G-tetrad layers, namely, Na(+) solution antiparallel-stranded basket form, K(+) crystal parallel-stranded propeller form, K(+) solution (3 + 1) Form 1, and K(+) solution (3 + 1) Form 2. Here we present a new intramolecular G-quadruplex adopted by a four-repeat human telomeric sequence in K(+) solution (Form 3). This ...[more]

PMID: 19271707

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Project description:The structure of human telomere DNA is of intense interest because of its role in the biology of both cancer and aging. The sequence [5'-AGGG(TTAGGG)3] has been used as a model for telomere DNA in both NMR and X-ray crystallographic studies, the results of which show dramatically different structures. In Na+ solution, NMR revealed an antiparallel G-quadruplex structure that featured both diagonal and lateral TTA loops. Crystallographic studies in the presence of K+ revealed a flattened, propeller-shaped structure featuring a parallel-stranded G-quadruplex with symmetrical external TTA loops. We report the results of biophysical experiments in solution and computational studies that are inconsistent with the reported crystal structure, indicating that a different structure exists in K+ solutions. Sedimentation coefficients were determined experimentally in both Na+ and K+ solutions and were compared with values calculated using bead models for the reported NMR and crystal structures. Although the solution NMR structure accurately predicted the observed S-value in Na+ solution, the crystal structure predicted an S-value that differed dramatically from that experimentally observed in K+ solution. The environments of loop adenines were probed by quantitative fluorescence studies using strategic and systematic single-substitutions of 2-aminopurine for adenine bases. Both fluorescence intensity and quenching experiments in K+ yielded results at odds with quantitative predictions from the reported crystal structure. Circular dichroism and fluorescence quenching studies in the presence of the crowding agent polyethylene glycol showed dramatic changes in the quadruplex structure in K+ solutions, but not in Na+ solutions, suggesting that the crystal environment may have selected for a particular conformational form. Molecular dynamics simulations were performed to yield model structures for the K+ quadruplex form that are consistent with our biophysical results and with previously reported chemical modification studies. These models suggest that the biologically relevant structure of the human telomere quadruplex in K+ solution is not the one determined in the published crystalline state.

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Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers.

Publications

Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers.

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