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

Abstract

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.

Promoters vs. telomeres: AP-endonuclease 1 interactions with abasic sites in G-quadruplex folds depend on topology

“…This slow processing of DNA damage in G4 folds may contribute to the late DNA damage processing in telomeres leading to senescence. 48 Modifications to DNA and the nucleic acid structure are key components to epigenetics; G oxidation to OG in dsDNA initiating base release and the unmasking of a G4 cue the epigenetic-like stress response, 2 which contrasts with G4 folds being refractory to the writing of 5mC in the genome. 49 The epigenetic landscape involving G4 folds and chemical modifications will require further studies to fully appreciate their biological impact.…”

New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary

“…However, this p53-dependent form of premature senescence was importantly not accompanied by a shortening of telomeres, but rather by telomere fragility. The telomeres were furthermore hypersensitive to replication stress caused by 8-oxoguanine, and it was hypothesized that stalling of replication could explain the arrest in cell growth and premature senescence [ 38 ].…”

Insights into the Photodynamics of Fluorescence Emission and Singlet Oxygen Generation of Fluorogen Activating Protein‐Malachite Green Systems

“…Di‐iodination on the MG core allows significant enhancement of the singlet oxygen ( 1 O 2 ) generation upon NIR light irradiation due to the heavy atom effect [14] . The site‐specific cellular perturbation by 1 O 2 has been applied to targeted cell killing, or to induce the formation of 8‐oxoG in telomere to study the corresponding biological responses [1b,14–15] . A recent report has shown that the tetra‐fluorination on the MG core can cause a significant drop in the fluorescence quantum yield ( Φ FL ) compared to the non‐substituted one, [16] indicating that modifications on the MG core may significantly vary the performance of the protein‐bound state.…”