Quadruplex sequences

The possibility of cation-induced changes in G-quadruplex structure has formed the basis for the hypothesis that DNA G-quadruplexes might function as molecular switches in vAo. In this section we review experiments related to reports of cation-driven conformational changes by G-quadruplexes. While this proposal is certainly related to the cation-dependent polymorphisms described in Section 4.6, the results presented in this section are more focused on G-quadruplex sequences and transitions that have been proposed as possible cation-dependent molecular switches, particularly those sequences derived from telomere DNA sequences. 

Ambrus, A., Chen, D., Dai, J., Biabs, T., Jones, R.A. and Yang, D. (2006) Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution, Nucleic Acids Res., 34, 2723-2735. 

Burge S, Parkinson GN, Hazel P et al (2006) Quadruplex DNA sequence, topology and structure. Nucleic Acids Res 34 5402-5415... 

The formation of aptamer-substrate complexes was also followed by the use of redox-active intercalators73 (Fig. 12.18d). A nucleic acid hairpin structure that contained in its single-stranded loop the antithrombin base sequence was assembled on a Au electrode, and methylene blue was intercalated as a redox label in the double-stranded stem of the hairpin structure. The hairpin was, then, opened in the presence of thrombin, by generating the respective G-quadruplex-thrombin complex, and as a result, the redox label was removed from the nucleic structure, showing a decrease in the voltammetric response with the increase in the concentration of thrombin. This method enabled the analysis of thrombin with a detection limit that corresponded to... 

Four DNA strands can also pair to form a tetraplex (quadruplex), but this occurs readily only for DNA sequences with a very high proportion of guanosine residues (Fig. 8-22c, d). The guanosine tetraplex, or G tetraplex, is quite stable over a wide range of conditions. The orientation of strands in the tetraplex can vary as shown in Figure 8-22e. 

Begusova M, Tartier L, Syt D, Spotheim-Maurizot M, Michalik V, Charlier M (1999) Monte Carlo simulation of radiolytic attack to 5 -d[T4G4]4 sequence in a unimolecular quadruplex. Int J Radiat Biol 75 913-917... 

The results from Zhou et al. revealed that the introduction of electron-donating groups such as substituted amino groups at the C-ll position of the quindoline significantly enhanced the ability of the molecule to inhibit telomerase activity (IC50 > 138 iM for quindoline, 0.44-12.3 iM for quindoline derivatives 1-10). The quindoline derivatives not only stabilized the G-quadruplex structure but also induced the G-rich telomeric repeated DNA sequence to fold into a quadruplex [31]. 

Sequence Versus Structure Targeting The Example of G-Quadruplexes... 

Much like the search for protein-binding compounds requires consideration of tertiary structure in addition to peptide sequence, thinking about selective nucleic acid binding solely in the context of primary sequence is often an oversimplification. In the context of DNA recognition, a particularly important example of this is the case of G-quadruplexes. As their name implies, these structures consist of stacked tetrads of guanosine bases, typically ordered around a monovalent cation. One representative structure, a quadruplex derived from human telomeric DNA, is shown in Fig. 5 many variants of this motif formed by either parallel or antiparallel DNA strands have been observed. 

Considered together, these four studies ably demonstrate the ability of DCC to rapidly yield lead structures for interesting targets. Despite the relatively small size of the libraries examined in each case, the diversity of structures accessible by the methodology is remarkable. G-quadruplex RNA has also been described [17], and therefore it is likely that future discovery efforts will also expand to targeting these sequences. Finally, as we will discuss later, G-quartets have served as scaffolds for the generation of novel materials via dynamic methods. 

DNA showed that there might be a biological consequence to oxidation of telomeric DNA. Telomeric DNA contains GGG sequences, and telomeres adopt a quadruplex structure. Oxidation of the 5 -G resulted in a quadruplex structure, but oxidation in the middle of the GGG triplex led to multiple structures. Telomerase activity was significantly reduced when 8-oxo-dG was at the 5 -end of the triplet, but not in the middle where multiple structures were formed. 

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