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Folding and misfolding pathways of G-quadruplex DNA

Abstract : G-quadruplexes adopt various folding topologies, but information on their folding pathways remains scarce. Here, we used electrospray mass spectrometry to detect and quantify the specifically bound potassium ions, and circular dichroism to characterize the stacking topology of each ensemble. For human telomeric (hTel) sequences containing the d((GGGTTA)3GGG) core, K+ binding affinity and cooperativity strongly depends on the chosen construct. The shortest sequences bind only one K + at low KCl concentration, and this 2-quartet G- quadruplex is antiparallel. Flanking bases increase the K + binding cooperativity. To decipher the fold- ing pathways, we investigated the kinetics of K + binding to telomeric (hybrid) and c-myc (parallel) G-quadruplexes. G-quadruplexes fold via branched pathways with multiple parallel reactions. Up to six states (one ensemble without K + , two ensembles with 1-K + and three ensembles with 2-K + ) are sep- arated based on their formation rates and ion mobil- ity spectrometry. All G-quadruplexes first form long- lived misfolded structures (off-pathway compared to the most stable structures) containing one K + and two quartets in an antiparallel stacking arrangement. The results highlight the particular ruggedness of G-quadruplex nucleic acid folding landscapes. Mis- folded structures can play important roles for design- ing artificial G-quadruplex based structures, and for conformational selection by ligands or proteins in a biological context
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Submitted on : Friday, October 21, 2016 - 10:17:52 AM
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2016-Nucl. Acids Res.-Marchand...
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Adrien Marchand, Valérie Gabelica. Folding and misfolding pathways of G-quadruplex DNA . Nucleic Acids Research, Oxford University Press, 2016, ⟨10.1093/nar/gkw970⟩. ⟨inserm-01385240⟩



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