Quadruplex DNA: sequence, topology and structure

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R Bishop
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Quadruplex DNA: sequence, topology and structure

 I was digging around in the literature this morning and came across quadruplex DNA.  I had never heard of such a thing before.  Then I found  this extremely excellent review article in open source so I thought I might pass it along for those that are interested in such things.  Fascinating stuff! 
Quadruplex DNA: sequence, topology and structure
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.
The knowledge that guanine-rich nucleic acids can self-associate has a long history, pre-dating the double helix itself by almost 50 years. For much of that time, the gels formed by such sequences were more of nuisance value than scientific worth. The molecular basis for the association was subsequently determined by fibre diffraction (1–3) and biophysical (4) studies using the concept (5,6) that the Hoogsteen hydrogen-bonded guanine (G)-tetrad (also termed a G-quartet) is the basic structural motif (Figure 1a). The synthetic polynucleotides poly(dG) and poly(G) were determined in these studies to form four-stranded helical structures (Figure 1b) with the G-tetrads stacked on one another, analogous to Watson–Crick base pairs in duplex DNA. These structures remained largely laboratory curiosities until it was found that short G-rich sequences at the ends of telomeric DNA in eukaryotic chromosomes can associate together in physiological ionic conditions to form discrete four-stranded structures (variously termed quadruplexes, tetraplexes or G4 structures) that incorporate the fundamental structural feature of having at least two contiguous G-tetrads stacked one on another (7,8).
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