Dramatic effect of single-base mutation on the conformational dynamics of human telomeric G-quadruplex.
Guanine-rich DNA sequences can form G-quadruplexes. These four-stranded structures are known to form in several genomic regions and to influence certain biological activities. Sometimes, the instability of G-quadruplexes causes the abnormal biological processes. Mutation is a culprit for the destabilization of G-quadruplexes, but the details of mutated G-quadruplexes are poorly understood. In this article, we investigated the conformational dynamics of single-base mutated human telomeric G-quadruplexes in the presence of K(+) with single-molecule FRET spectroscopy. We observed that the replacement of single guanine by thymine in a G-track induces various folded structures, i.e. structural polymorphism. Moreover, direct observation of their dynamics revealed that a single-base mutation causes fast unfolding of folded states under physiological conditions. Furthermore, we found that the degree of destabilization varies according to mutation positions. When the central guanine of a G-track is replaced, the G-quadruplexes unfold quickly at any K(+) concentrations and temperature. Meanwhile, outer-quartet mutated G-quadruplexes have heterogeneous dynamics at intermediate K(+) concentrations and longstanding folded states at high K(+) concentrations. Several factors such as base-stacking interaction and K(+) coordination are responsible for the different dynamics according to the mutation position.
Department of Physics and Astronomy, Seoul National University, San 56-1, Shillim-dong, Kwanak-gu, Seoul, 151-742, South Korea. jayil@phya.snu.ac.kr
Ja Yil
JY
Lee
D S
DS
Kim
D004247:DNA / Q000737:chemistry; D031541:Fluorescence Resonance Energy Transfer; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D009154:Mutation; D011188:Potassium / Q000737:chemistry; D016615:Telomere / Q000737:chemistry*; D013696:Temperature; D013941:Thymine / Q000737:chemistry
D006147:Guanine; D004247:DNA; D013941:Thymine; D011188:Potassium