Long-Loop G-Quadruplexes Are Misfolded Population Minorities with Fast Transition Kinetics in Human Telomeric Sequences

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• 作者：Deepak Koirala ; Chiran Ghimire ; Christopher Bohrer ; Yuta Sannohe ; Hiroshi Sugiyama ; Hanbin Mao
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：February 13, 2013
• 年：2013
• 卷：135
• 期：6
• 页码：2235-2241
• 全文大小：459K
• 年卷期：v.135,no.6(February 13, 2013)
• ISSN：1520-5126

文摘

Single-stranded guanine (G)-rich sequences at the 3鈥?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鈥?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.