Targeted DNA damage at individual telomeres disrupts their integrity and triggers cell death

Nucleic Acids Res. 2015 Jul 27;43(13):6334-47. doi: 10.1093/nar/gkv598. Epub 2015 Jun 16.


Cellular DNA is organized into chromosomes and capped by a unique nucleoprotein structure, the telomere. Both oxidative stress and telomere shortening/dysfunction cause aging-related degenerative pathologies and increase cancer risk. However, a direct connection between oxidative damage to telomeric DNA, comprising <1% of the genome, and telomere dysfunction has not been established. By fusing the KillerRed chromophore with the telomere repeat binding factor 1, TRF1, we developed a novel approach to generate localized damage to telomere DNA and to monitor the real time damage response at the single telomere level. We found that DNA damage at long telomeres in U2OS cells is not repaired efficiently compared to DNA damage in non-telomeric regions of the same length in heterochromatin. Telomeric DNA damage shortens the average length of telomeres and leads to cell senescence in HeLa cells and cell death in HeLa, U2OS and IMR90 cells, when DNA damage at non-telomeric regions is undetectable. Telomere-specific damage induces chromosomal aberrations, including chromatid telomere loss and telomere associations, distinct from the damage induced by ionizing irradiation. Taken together, our results demonstrate that oxidative damage induces telomere dysfunction and underline the importance of maintaining telomere integrity upon oxidative damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death
  • Cell Line
  • Cellular Senescence
  • DNA Damage*
  • DNA Repair
  • Green Fluorescent Proteins / genetics
  • Guanine / analogs & derivatives
  • Guanine / metabolism
  • Humans
  • Oxidative Stress*
  • Repetitive Sequences, Nucleic Acid
  • Telomere / chemistry
  • Telomere / metabolism*
  • Telomere Shortening*
  • Telomeric Repeat Binding Protein 1 / genetics


  • Telomeric Repeat Binding Protein 1
  • killer red protein, Anthomedusae
  • Green Fluorescent Proteins
  • 8-hydroxyguanine
  • Guanine