Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis. Fouquerel et al
Telomeres are essential for genome stability. Oxidative stress caused by excess reactive oxygen species (ROS) accelerates telomere shortening. While telomeres are hypersensitive to ROS-mediated 8-oxoguanine (8-oxoG) formation, the biological impact of this common lesion at telomeres is poorly understood because ROS has 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 micronuclei formation upon cell division. By confining base damage to the telomeres, we show that telomeric 8-oxoG accumulation directly drives telomere crisis.