G-quadruplex structure

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. 

Han H, Cliff CL, Hurley LH (1999) Accelerated assembly of G-quadruplex structures by a small molecule. Biochemistry 38 6981-6986... 

Seenisamy J, Bashyam S, Gokhale V, Vankayalapati H, Sun D, Siddiqui-Jain A, Streiner N, Shin-Ya K, White E, Wilson WD, Hurley EH (2005) Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J Am Chem Soc 127(9) 2944-2959 Sen D, Crothers DM (1986) Influence of DNA-binding drugs on chromatin condensation. Biochemistry 25(7) 1503-1509... 

Figure 3.22 Dynamic decoration and formation of appended G-quadruplex structures capable of forming hydrogels.

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]. 

LNA has frequently been used to stabilise duplex structures, but in triplex structures the effect is mixed. Partial substitution of a DNA TFO by LNA increases triplex stability, whilst complete substitution leads to destabilisation. Optimal stabilisation was found with substitution every 2-3 nucleotides of the TFO. The incorporation of LNA into a G-quadruplex structure was shown to alter the orientation of the quadruplex from antiparallel to parallel. ... 

As described before, an altered telomere state may be a more important consequence than critical telomere shortening (33). Thus, disruption of telesomes by either depletion of proteins involved in telomere binding (e.g., telomerase) or sequestration of telomere ends by stabilization of G-quadruplex structures, or both, may lead to chromosome end-to-end fusion in piesenescence cells. In fact, TMPyP4 and the fluoroquinophenoxazines have both been demonstrated to produce anaphase bridges, a hallmark of chromosome end fusions, in relatively short periods of time (78). 

The 9-anilino proflavine derivative was designed to optimize the interaction with the intramolecular G-quadruplex from human telomere and minimize that with duplex DNA. These compounds have 60 to 100 nM potency in a modified TRAP assay and corresponding low cytotoxicity (93). The triazines have been demonstrated to produce telomere shortening, which is associated with delayed growth arrest and cell senescence (80). The fluoroquinophenoxazines are redesigned topoisomerase II poisons that now interact more specifically with G-quadruplex structures, and this activity is correlated with production of anaphase bridges (78), a property also shared by the cationic porphyrin TMPyP4 (96) and... 

Han H, Bennett RJ, Hurley LH. 2000. Inhibition of unwinding of G-quadruplex structures by Sgsl helicase in the presence of N,N -bis 2-( 1 -piperidino)ethyl -3,4,9,10-perylenetetracarboxylicdiimide, a G-quadruplex-interactive ligand. Biochemistry 39 5295—302... 

Han H, Langley DR, Rangan A, Hurley LH. 2001. Selective interactions of cationic porphyrins with G-quadruplex structures. J. Am. Chem. Soc. 123 8902-13... 

Telomeric repeats from other organisms are also prone to quadruplex polymorphism. The Tetrahymena TG4T2G4T telomeric sequence, for example, may adopt several conformations. This sequence forms two novel G-quadruplex structures in Na -containing solution. In the first structure (head-to-head), the two loops are at one end of the G-tetrad core in the second structure (head-to-tail), the two loops are located on opposite ends of the G-tetrad core. In contrast to the human telomere sequence, the proportions of the two forms are similar for a wide range of temperatures their unfolding rates are also similar, with an activation enthalpy of 37 kcal mol . The (G4T4) sequence may also interconvert between parallel and antiparallel structures. 

Ligands that selectively bind to G-quadruplex structures may modulate telom-erase activity, alter telomere structure or repress the transcription of key oncogenes (for a review, see this book s chapters by M. Searle and J.F. Riou). The way ligands interact with quadruplexes also give clues on the dynamics of the G-quartets with the possible exception of a porphyrin derivative, true intercalation (between two quartets) is considered unfavourable or impossible. This indicates that, contrary to DNA base pairs, transient unstacking/opening of two G-quartets is an extremely rare or short event, incompatible with the incorporation of a planar chromophore. End stacking, which does not require the separation of two quartets nor the release of cation is therefore the most frequently observed mode of interaction. ... 

G-quadruplex structures are polymorphic regarding the G-tetrad core and the loops. Recent G-quadruplex structures have been reported to contain a variety of new structural elements, as opposed to simpler structures that were reported or proposed a decade ago. This Chapter first describes and classifies the core and loop elements in G-quadruplexes, then examines several examples of recently reported structures. 

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