Telomeres are the protective ends of linear eukaryotic chromosomes. Human telomeric DNA consists mainly of thousands of TTAGGG repeats terminated with a 100-200 nucleotides 3'-end overhang. In vitro, human telomeric DNA sequences can form four-stranded helical structures called G-quadruplexes, built from the stacking of multiple G tetrads. G-quadruplexes at telomeres have been detected in vivo  and their existence in living cells can be regulated by a number of proteins. Intramolecular G-quadruplexes formed by human telomeric DNA sequences are promising anticancer targets , because formation of such structures by the telomeric 3'-end overhang inhibits the activity of telomerase, an enzyme necessary for the proliferation of most human cancer cells.
G-quadruplex structures are highly polymorphic: different G-quadruplex topologies correspond to very different shapes and dimensions of various structural elements, such as grooves and loops. Only relatively small energetic differences exist between different topologies. To reliably estimate the thermodynamic factors that influence the relative stability of different conformers, is essential both to understand the structure of the telomere and how switching between conformers allows for regulation of telomere replication, and develop reagents that bind specifically to different conformers for use as drugs.
Here we show how we have exploited several complementary experimental techniques to obtain specific and detailed information on the structural and thermodynamic properties of human telomere G-quadruplexes. The results from UV Resonant Raman scattering, CD spectroscopy and small angle X-ray scattering provided precious insights into the properties of the native, intermediate and unfolded states populated by G-quadruplexes during thermal unfolding. The effect of complexed drugs on the structural and thermodynamic features is also discussed.
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