title: Long-loop G-quadruplexes are misfolded population minorities with fast transition kinetics in human telomeric sequences.
abstract: Single-stranded guanine (G)-rich sequences at the 3' end of human telomeres provide ample opportunities for physiologically relevant structures, such as G-quadruplexes, to form and interconvert. Population equilibrium in this long sequence is expected to be intricate and beyond the resolution of ensemble-average techniques, such as circular dichroism, NMR, or X-ray crystallography. By combining a force-jump method at the single-molecular level and a statistical population deconvolution at the sub-nanometer resolution, we reveal a complex population network with unprecedented transition dynamics in human telomeric sequences that contain four to eight TTAGGG repeats. Our kinetic data firmly establish that G-triplexes are intermediates to G-quadruplexes while long-loop G-quadruplexes are misfolded population minorities whose formation and disassembly are faster than G-triplexes or regular G-quadruplexes. The existence of misfolded DNA supports the emerging view that structural and kinetic complexities of DNA can rival those of RNA or proteins. While G-quadruplexes are the most prevalent species in all the sequences studied, the abundance of a misfolded G-quadruplex in a particular telomeric sequence decreases with an increase in the loop length or the number of long-loops in the structure. These population patterns support the prediction that in the full-length 3' overhang of human telomeres, G-quadruplexes with shortest TTA loops would be the most dominant species, which justifies the modeling role of regular G-quadruplexes in the investigation of telomeric structures.
authors: Department of Chemistry & Biochemistry, Kent State University, Kent, Ohio 44242, USA.
authors: Deepak
authors: D
authors: Koirala
authors: Chiran
authors: C
authors: Ghimire
authors: Christopher
authors: C
authors: Bohrer
authors: Yuta
authors: Y
authors: Sannohe
authors: Hiroshi
authors: H
authors: Sugiyama
authors: Hanbin
authors: H
authors: Mao
mesh_terms: D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D016615:Telomere / Q000737:chemistry*
chemical_list: D011506:Proteins; D006147:Guanine; D004247:DNA