Skip Navigation

Publication Detail

Title: Targeted and Persistent 8-Oxoguanine Base Damage at Telomeres Promotes Telomere Loss and Crisis.

Authors: Fouquerel, Elise; Barnes, Ryan P; Uttam, Shikhar; Watkins, Simon C; Bruchez, Marcel P; Opresko, Patricia L

Published In Mol Cell, (2019 Jul 11)

Abstract: Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. Although telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological effect of this common lesion at telomeres is poorly understood because ROS have pleiotropic effects. Here we developed a chemoptogenetic tool that selectively produces 8-oxoG only at telomeres. Acute telomeric 8-oxoG formation increased telomere fragility in cells lacking OGG1, the enzyme that removes 8-oxoG, but did not compromise cell survival. However, chronic telomeric 8-oxoG induction over time shortens telomeres and impairs cell growth. Accumulation of telomeric 8-oxoG in chronically exposed OGG1-deficient cells triggers replication stress, as evidenced by mitotic DNA synthesis at telomeres, and significantly increases telomere losses. These losses generate chromosome fusions, leading to chromatin bridges and micronucleus formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.

PubMed ID: 31101499 Exiting the NIEHS site

MeSH Terms: Cell Division/radiation effects; Cell Line, Tumor; Cell Survival/radiation effects; Chromosome Aberrations/radiation effects*; DNA Damage; DNA Glycosylases/deficiency; DNA Glycosylases/genetics*; DNA Repair/radiation effects*; DNA Replication/radiation effects; Gene Expression; Genomic Instability/radiation effects*; Guanine/agonists; Guanine/analogs & derivatives*; Guanine/biosynthesis; HeLa Cells; Humans; Light/adverse effects; Micronuclei, Chromosome-Defective/radiation effects; Optogenetics; Osteoblasts/cytology; Osteoblasts/metabolism; Osteoblasts/radiation effects; Oxidative Stress/radiation effects; Singlet Oxygen/agonists; Singlet Oxygen/metabolism; Telomere Homeostasis/radiation effects; Telomere/metabolism; Telomere/radiation effects*

Back
to Top