Telomeric 8-oxo-guanine drives rapid premature senescence in the absence of telomere shortening

This study uncovers a new mechanism linking oxidative stress to telomere-driven senescence. A common oxidative lesion at telomeres causes rapid premature cellular aging by inducing telomere fragility, rather than telomere shortening. Oxidative stress is a primary cause of cellular senescence and contributes to the etiology of numerous human diseases. Oxidative damage to telomeric DNA has been proposed to cause premature senescence by accelerating telomere shortening. Here, we tested this model directly using a precision chemoptogenetic tool to produce the common lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblasts and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results, we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions that drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

Automated summary

This study reveals how oxidative stress induces significant cellular aging by generating oxidative damage at telomeres. The mechanism through which oxidative damage triggers cellular senescence is not through telomere shortening, but through inducing telomere fragility, leading to accelerated cellular aging.