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端粒 8-氧鸟嘌呤在没有端粒缩短的情况下驱动快速衰老。

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

机构信息

Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

出版信息

Nat Struct Mol Biol. 2022 Jul;29(7):639-652. doi: 10.1038/s41594-022-00790-y. Epub 2022 Jun 30.

DOI:10.1038/s41594-022-00790-y
PMID:35773409
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9287163/
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.

摘要

氧化应激是细胞衰老的主要原因，并导致许多人类疾病的发病机制。端粒 DNA 的氧化损伤被认为通过加速端粒缩短导致过早衰老。在这里，我们使用一种精确的化学遗传学工具直接测试了这个模型，该工具可专门在人类成纤维细胞和上皮细胞中端粒上产生常见的损伤 8-氧鸟嘌呤（8oxoG）。端粒 8oxoG 的单次诱导足以引发多个 p53 依赖性衰老的特征。端粒 8oxoG 激活 ATM 和 ATR 信号，并在复制而非静止细胞中富集端粒功能障碍的标志物。急性 8oxoG 产生不会缩短端粒，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。基于我们的结果，我们提出氧化应激通过产生氧化碱基损伤来促进快速衰老，这些损伤在没有缩短和庇护素丢失的情况下驱动依赖于复制的端粒脆弱性和功能障碍。

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