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.

氧化应激是细胞衰老的主要原因，也是许多人类疾病的病因。已提出对端粒 DNA 的氧化损伤通过加速端粒缩短导致过早衰老。在这里，我们直接使用精确的化学遗传学工具测试了该模型，以专门在人成纤维细胞和上皮细胞的端粒处产生常见损伤 8-氧代-鸟嘌呤 (8oxoG)。端粒 8oxoG 的单次诱导足以触发 p53 依赖性衰老的多个标志。端粒 8oxoG 激活 ATM 和 ATR 信号，并富集复制中端粒功能障碍的标记，但不包括静止细胞。急性 8oxoG 生产不能缩短端粒，而是在端粒处产生脆弱位点和有丝分裂 DNA 合成，表明复制受损。