Dramatic effect of single-base mutation on the conformational dynamics of human telomeric G-quadruplex

Nucleic Acids Res. 2009 Jun;37(11):3625-34. doi: 10.1093/nar/gkp216. Epub 2009 Apr 9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA / chemistry
  • Fluorescence Resonance Energy Transfer
  • G-Quadruplexes*
  • Guanine / chemistry
  • Humans
  • Kinetics
  • Mutation
  • Potassium / chemistry
  • Telomere / chemistry*
  • Temperature
  • Thymine / chemistry

Substances

  • Guanine
  • DNA
  • Thymine
  • Potassium