A novel small molecule that alters shelterin integrity and triggers a DNA-damage response at telomeres

J Am Chem Soc. 2008 Nov 26;130(47):15758-9. doi: 10.1021/ja805615w.

Abstract

We describe a novel synthetic small molecule which shows an unprecedented stabilization of the human telomeric G-quadruplex with high selectivity relative to double-stranded DNA. We report that this compound can be used in vitro to inhibit telomerase activity and to uncap human POT1 (protection of telomeres 1) from the telomeric G-overhang. We also show that the small molecule G-quadruplex binder induces a partial alteration of shelterin through POT1 uncapping from telomeres in human HT1080 cancer cells and the presence of gammaH2AX foci colocalized at telomeres.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • DNA Damage / genetics*
  • Humans
  • Molecular Structure
  • Shelterin Complex
  • Telomere / chemistry*
  • Telomere / genetics
  • Telomere / metabolism*
  • Telomere-Binding Proteins / antagonists & inhibitors
  • Telomere-Binding Proteins / chemistry*
  • Telomere-Binding Proteins / metabolism*

Substances

  • POT1 protein, human
  • Shelterin Complex
  • Telomere-Binding Proteins