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Structural transition from antiparallel to parallel G-quadruplex of d(G4T4G4) induced by Ca2+.

ABSTRACT: Guanine quadruplex (G-quadruplex) structures are formed by guanine-rich oligonucleotides. Because of their in vivo and in vitro importance, numerous studies have been demonstrated that the structure and stability of the G-quadruplex are dependent on the sequence of oligonucleotide and environmental conditions such as existing cations. Previously, we quantitatively investigated the divalent cation effects on the antiparallel G-quadruplex of d(G4T4G4), and found that Ca2+ induces a structural transition from the antiparallel to parallel G-quadruplex, and finally G-wire formation. In the present study, we report in detail the kinetic and thermodynamic analyses of the structural transition induced by Ca2+ using stopped-flow apparatus, circular dichroism, size-exclusion chromatography (SEC) and atomic force microscopy. The quantitative parameters showed that at least two Ca2+ ions were required for the transition. The kinetic parameters also indicated that d(G4T4G4) underwent the transition through multiple steps involving the Ca2+ binding, isomerization and oligomerization of d(G4T4G4). The parallel-stranded G-wire structure of d(G4T4G4), which is a well controlled alignment of numerous DNA strands with G-quartets, as the final product induced by Ca2+, was observed using SEC and atomic force microscopy. These results provide insight into the mechanism of the structural transition and G-wire formation and are useful for constructing a nanomaterial regulated by Ca2+.

SUBMITTER: Miyoshi D

PROVIDER: S-EPMC150229 | biostudies-literature | 2003 Feb

REPOSITORIES: biostudies-literature

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Structural transition from antiparallel to parallel G-quadruplex of d(G4T4G4) induced by Ca2+.

Miyoshi Daisuke D Nakao Akihiro A Sugimoto Naoki N

Nucleic acids research 20030201 4

Guanine quadruplex (G-quadruplex) structures are formed by guanine-rich oligonucleotides. Because of their in vivo and in vitro importance, numerous studies have been demonstrated that the structure and stability of the G-quadruplex are dependent on the sequence of oligonucleotide and environmental conditions such as existing cations. Previously, we quantitatively investigated the divalent cation effects on the antiparallel G-quadruplex of d(G4T4G4), and found that Ca2+ induces a structural tran ...[more]

PMID: 12582234

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Project description:Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG). The formation and stabilization of DNA G-quadruplexes in the human telomeric sequence have been shown to inhibit the activity of telomerase, thus the telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention. However, knowledge of the intact human telomeric G-quadruplex structure(s) formed under physiological conditions is a prerequisite for structure-based rational drug design. Here we report the folding structure of the human telomeric sequence in K+ solution determined by NMR. Our results demonstrate a novel, unprecedented intramolecular G-quadruplex folding topology with hybrid-type mixed parallel/antiparallel G-strands. This telomeric G-quadruplex structure contains three G-tetrads with mixed G-arrangements, which are connected consecutively with a double-chain-reversal side loop and two lateral loops, each consisting of three nucleotides TTA. This intramolecular hybrid-type telomeric G-quadruplex structure formed in K+ solution is distinct from those reported on the 22 nt Tel22 in Na+ solution and in crystalline state in the presence of K+, and appears to be the predominant conformation for the extended 26 nt telomeric sequence Tel26 in the presence of K+, regardless of the presence or absence of Na+. Furthermore, the addition of K+ readily converts the Na+-form conformation to the K+-form hybrid-type G-quadruplex. Our results explain all the reported experimental data on the human telomeric G-quadruplexes formed in the presence of K+, and provide important insights for understanding the polymorphism and interconversion of various G-quadruplex structures formed within the human telomeric sequence, as well as the effects of sequence and cations. This hybrid-type G-quadruplex topology suggests a straightforward pathway for the secondary structure formation with effective packing within the extended human telomeric DNA. The hybrid-type telomeric G-quadruplex is most likely to be of pharmacological relevance, and the distinct folding topology of this G-quadruplex suggests that it can be specifically targeted by G-quadruplex interactive small molecule drugs.

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Structural transition from antiparallel to parallel G-quadruplex of d(G4T4G4) induced by Ca2+.

Publications

Structural transition from antiparallel to parallel G-quadruplex of d(G4T4G4) induced by Ca2+.

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