Limits...
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.

Show MeSH
NMR-derived topology and one of the deposited structures of the c-myc quadruplex (86) (PDB entry 1XAV).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC1636468&req=5

fig6: NMR-derived topology and one of the deposited structures of the c-myc quadruplex (86) (PDB entry 1XAV).

Mentions: Quadruplex formation has been examined in vitro in a number of non-telomeric sequences (Table 4). The NHE III1 G-rich sequence in the promoter region of the c-myc oncogene, which is responsible for 80–90% of its transcriptional activity, has been especially studied. The existence of a quadruplex within this promoter region was initially proposed (20) based on the data from chemical probe and gel mobility measurements, and from fluorescence resonance energy transfer spectroscopy (86). Subsequent studies established a relationship between quadruplex stabilization within this sequence and suppression of c-myc transcriptional activation (83), with the porphyrin TMPyP4 acting to stabilize the quadruplex structure. NMR in solution (87–89), as well as that of a porphyrin TMPyP4 complex (89) has determined topology and detailed structures of several c-myc quadruplex sequences. Non-telomeric G-rich regions often contain more than four consecutive G-tracts (see above) which, as in the case of c-myc, results in the formation of multiple quadruplex species in the native Pu27 region (this dynamic behaviour, which may involve shuffling between G-tracts, is distinct from the conformational rearrangements shown by the human telomeric 22mer, e.g.). Shorter sequences from within the Pu27 region have been successfully analysed by NMR methods. Myc-2345 and Myc-1245 each contain four G-tracts and form very stable parallel-stranded unimolecular quadruplexes in solution (Figure 6), with G-tracts joined through propeller loops, and with all guanines involved in the G-tetrads having an anti conformation (87). These structures therefore share features with the human telomeric 22mer K+ crystal structure (22). In both myc-1245 and myc-2345, structures the first and third loops are single-nucleotide propeller loops; the second (central) loop in myc-2345 is a GA propeller loop and that in the non-natural myc-1245 consists of a large six-base TTTTTA loop. This loop is destabilizing compared to that in the shorter myc-2345 sequence, as shown by the 16°C difference in their melting temperatures. Both of these c-myc quadruplexes have higher melting temperatures than the human telomeric quadruplexes in similar K+ conditions. One remarkable feature of the Pu24I NMR structure, which has five G-tracts, is the fold-back of the 3′ terminal G in the last G-tract, enabling participation in a G-tetrad and the establishment of a neighbouring G·A•G hydrogen-bonded triad that is positioned as a planar platform-like diagonal loop above this G-tetrad. The other face of the quadruplex has a stack of base pairs and bases arising from the 5′ end sequence. The NMR solution structure of a complex of the Pu241 quadruplex with the porphyrin ligand TMPyP4 (89) shows that it stacks on the other terminal G-tetrad, sandwiched against one of base pair platforms, with overall little perturbation from the ligand-free Pu241 quadruplex structure.


Quadruplex DNA: sequence, topology and structure.

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

NMR-derived topology and one of the deposited structures of the c-myc quadruplex (86) (PDB entry 1XAV).
© Copyright Policy
Related In: Results  -  Collection

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

fig6: NMR-derived topology and one of the deposited structures of the c-myc quadruplex (86) (PDB entry 1XAV).
Mentions: Quadruplex formation has been examined in vitro in a number of non-telomeric sequences (Table 4). The NHE III1 G-rich sequence in the promoter region of the c-myc oncogene, which is responsible for 80–90% of its transcriptional activity, has been especially studied. The existence of a quadruplex within this promoter region was initially proposed (20) based on the data from chemical probe and gel mobility measurements, and from fluorescence resonance energy transfer spectroscopy (86). Subsequent studies established a relationship between quadruplex stabilization within this sequence and suppression of c-myc transcriptional activation (83), with the porphyrin TMPyP4 acting to stabilize the quadruplex structure. NMR in solution (87–89), as well as that of a porphyrin TMPyP4 complex (89) has determined topology and detailed structures of several c-myc quadruplex sequences. Non-telomeric G-rich regions often contain more than four consecutive G-tracts (see above) which, as in the case of c-myc, results in the formation of multiple quadruplex species in the native Pu27 region (this dynamic behaviour, which may involve shuffling between G-tracts, is distinct from the conformational rearrangements shown by the human telomeric 22mer, e.g.). Shorter sequences from within the Pu27 region have been successfully analysed by NMR methods. Myc-2345 and Myc-1245 each contain four G-tracts and form very stable parallel-stranded unimolecular quadruplexes in solution (Figure 6), with G-tracts joined through propeller loops, and with all guanines involved in the G-tetrads having an anti conformation (87). These structures therefore share features with the human telomeric 22mer K+ crystal structure (22). In both myc-1245 and myc-2345, structures the first and third loops are single-nucleotide propeller loops; the second (central) loop in myc-2345 is a GA propeller loop and that in the non-natural myc-1245 consists of a large six-base TTTTTA loop. This loop is destabilizing compared to that in the shorter myc-2345 sequence, as shown by the 16°C difference in their melting temperatures. Both of these c-myc quadruplexes have higher melting temperatures than the human telomeric quadruplexes in similar K+ conditions. One remarkable feature of the Pu24I NMR structure, which has five G-tracts, is the fold-back of the 3′ terminal G in the last G-tract, enabling participation in a G-tetrad and the establishment of a neighbouring G·A•G hydrogen-bonded triad that is positioned as a planar platform-like diagonal loop above this G-tetrad. The other face of the quadruplex has a stack of base pairs and bases arising from the 5′ end sequence. The NMR solution structure of a complex of the Pu241 quadruplex with the porphyrin ligand TMPyP4 (89) shows that it stacks on the other terminal G-tetrad, sandwiched against one of base pair platforms, with overall little perturbation from the ligand-free Pu241 quadruplex structure.

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