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Quadruplex DNA: sequence, topology and structure.

Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S - Nucleic Acids Res. (2006)

Bottom Line: This survey focuses on the folding and structural features on quadruplexes formed from telomeric and non-telomeric DNA sequences, and examines fundamental aspects of topology and the emerging relationships with sequence.Emphasis is placed on information from the high-resolution methods of X-ray crystallography and NMR, and their scope and current limitations are discussed.Such information, together with biological insights, will be important for the discovery of drugs targeting quadruplexes from particular genes.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.

ABSTRACT
G-quadruplexes are higher-order DNA and RNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Potential quadruplex sequences have been identified in G-rich eukaryotic telomeres, and more recently in non-telomeric genomic DNA, e.g. in nuclease-hypersensitive promoter regions. The natural role and biological validation of these structures is starting to be explored, and there is particular interest in them as targets for therapeutic intervention. This survey focuses on the folding and structural features on quadruplexes formed from telomeric and non-telomeric DNA sequences, and examines fundamental aspects of topology and the emerging relationships with sequence. Emphasis is placed on information from the high-resolution methods of X-ray crystallography and NMR, and their scope and current limitations are discussed. Such information, together with biological insights, will be important for the discovery of drugs targeting quadruplexes from particular genes.

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The crystal structure (28) of the bimolecular quadruplex formed by the O.nova telomeric sequence d(G4T4G4) (PDB entry 1JPQ). (a) Overall topology is indicated by the ribbon representation in orange. The details of the molecular structure are also shown. Potassium ions are shown as green spheres. (b) A projection down the central channel, indicating the relative widths of the four grooves
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fig3: The crystal structure (28) of the bimolecular quadruplex formed by the O.nova telomeric sequence d(G4T4G4) (PDB entry 1JPQ). (a) Overall topology is indicated by the ribbon representation in orange. The details of the molecular structure are also shown. Potassium ions are shown as green spheres. (b) A projection down the central channel, indicating the relative widths of the four grooves

Mentions: Association of two strands to produce bimolecular quadruplexes introduces increased topological variation (Figure 2a). The classic bimolecular quadruplex structure (Figure 3) is that formed by two strands of the O.nova sequence d(G4T4G4), with a diagonal T4 loop at each end of the symmetric quadruplex (28–31). It is remarkable that even apparently conservative changes in this sequence have major topological consequences: thus d(G3T4G4), with one guanine at the 5′ end less than in the wild-type sequence forms a bimolecular quadruplex having both lateral and diagonal loops (41). This is one of the few cases where a bimolecular quadruplex has an unequal number of parallel (three) and anti-parallel (one) strands; subsequent studies (42) showed that this topology is not dependent on the presence of ions, but is retained in K+ or Na+ solution, as does a mixed di-cation form (43). The sequence isomer, now with one guanine less at the 3′ end [i.e. d(G4T4G3)], also forms an asymmetric bimolecular quadruplex, but with less dramatic differences compared to the Oxytricha parent structure. This structure has a core of three stacked G-tetrads, so the two guanines not included in this core are involved in one of the two diagonal loops (44). Reducing the number of guanines still further, to d(G3T4G3), results in a more conventional diagonal-looped quadruplex, but with asymmetry in guanine glycosidic angles (45,46). Decreasing the size of the thymine loops also results in topological change, as observed in the crystal structures (Figure 4) of the bimolecular quadruplexes formed by d(G4T3G4), with lateral loops being consistently favoured (26). The implication of this, that loops with three or less nucleotides dis-favour diagonal in preference to lateral loops, is borne out by the exclusive presence of lateral loops in both interconverting bimolecular quadruplexes formed by the d(TG4T2G4T) Tetrahymena sequence (24). These are closely similar to the head-to-head and head-to-tail lateral loop bimolecular quadruplexes of d(G4T3G4) (26). Interestingly, the 5′ and 3′ flanking thymine residues in this pair of sequences have no effect on quadruplex topology.


Quadruplex DNA: sequence, topology and structure.

Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S - Nucleic Acids Res. (2006)

The crystal structure (28) of the bimolecular quadruplex formed by the O.nova telomeric sequence d(G4T4G4) (PDB entry 1JPQ). (a) Overall topology is indicated by the ribbon representation in orange. The details of the molecular structure are also shown. Potassium ions are shown as green spheres. (b) A projection down the central channel, indicating the relative widths of the four grooves
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1636468&req=5

fig3: The crystal structure (28) of the bimolecular quadruplex formed by the O.nova telomeric sequence d(G4T4G4) (PDB entry 1JPQ). (a) Overall topology is indicated by the ribbon representation in orange. The details of the molecular structure are also shown. Potassium ions are shown as green spheres. (b) A projection down the central channel, indicating the relative widths of the four grooves
Mentions: Association of two strands to produce bimolecular quadruplexes introduces increased topological variation (Figure 2a). The classic bimolecular quadruplex structure (Figure 3) is that formed by two strands of the O.nova sequence d(G4T4G4), with a diagonal T4 loop at each end of the symmetric quadruplex (28–31). It is remarkable that even apparently conservative changes in this sequence have major topological consequences: thus d(G3T4G4), with one guanine at the 5′ end less than in the wild-type sequence forms a bimolecular quadruplex having both lateral and diagonal loops (41). This is one of the few cases where a bimolecular quadruplex has an unequal number of parallel (three) and anti-parallel (one) strands; subsequent studies (42) showed that this topology is not dependent on the presence of ions, but is retained in K+ or Na+ solution, as does a mixed di-cation form (43). The sequence isomer, now with one guanine less at the 3′ end [i.e. d(G4T4G3)], also forms an asymmetric bimolecular quadruplex, but with less dramatic differences compared to the Oxytricha parent structure. This structure has a core of three stacked G-tetrads, so the two guanines not included in this core are involved in one of the two diagonal loops (44). Reducing the number of guanines still further, to d(G3T4G3), results in a more conventional diagonal-looped quadruplex, but with asymmetry in guanine glycosidic angles (45,46). Decreasing the size of the thymine loops also results in topological change, as observed in the crystal structures (Figure 4) of the bimolecular quadruplexes formed by d(G4T3G4), with lateral loops being consistently favoured (26). The implication of this, that loops with three or less nucleotides dis-favour diagonal in preference to lateral loops, is borne out by the exclusive presence of lateral loops in both interconverting bimolecular quadruplexes formed by the d(TG4T2G4T) Tetrahymena sequence (24). These are closely similar to the head-to-head and head-to-tail lateral loop bimolecular quadruplexes of d(G4T3G4) (26). Interestingly, the 5′ and 3′ flanking thymine residues in this pair of sequences have no effect on quadruplex topology.

Bottom Line: This survey focuses on the folding and structural features on quadruplexes formed from telomeric and non-telomeric DNA sequences, and examines fundamental aspects of topology and the emerging relationships with sequence.Emphasis is placed on information from the high-resolution methods of X-ray crystallography and NMR, and their scope and current limitations are discussed.Such information, together with biological insights, will be important for the discovery of drugs targeting quadruplexes from particular genes.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Biomolecular Structure Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, UK.

ABSTRACT
G-quadruplexes are higher-order DNA and RNA structures formed from G-rich sequences that are built around tetrads of hydrogen-bonded guanine bases. Potential quadruplex sequences have been identified in G-rich eukaryotic telomeres, and more recently in non-telomeric genomic DNA, e.g. in nuclease-hypersensitive promoter regions. The natural role and biological validation of these structures is starting to be explored, and there is particular interest in them as targets for therapeutic intervention. This survey focuses on the folding and structural features on quadruplexes formed from telomeric and non-telomeric DNA sequences, and examines fundamental aspects of topology and the emerging relationships with sequence. Emphasis is placed on information from the high-resolution methods of X-ray crystallography and NMR, and their scope and current limitations are discussed. Such information, together with biological insights, will be important for the discovery of drugs targeting quadruplexes from particular genes.

Show MeSH