Senescent cells display senescence‐associated (SA) phenotypic programs such as stable proliferation arrest (SAPA) and a secretory phenotype (SASP). Senescence‐inducing persistent DNA double‐strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but the SASP requires days to develop. Here, we show that following the immediate canonical DDR, a delayed chromatin accumulation of the ATM and MRN complexes coincides with the expression of SASP factors. Importantly, histone deacetylase inhibitors (HDACi) trigger SAPA and SASP in the absence of DNA damage. However, HDACi‐induced SASP also requires ATM/MRN activities and causes their accumulation on chromatin, revealing a DNA damage‐independent, non‐canonical DDR activity that underlies SASP maturation. This non‐canonical DDR is required for the recruitment of the transcription factor NF‐κB on chromatin but not for its nuclear translocation. Non‐canonical DDR further does not require ATM kinase activity, suggesting structural ATM functions. We propose that delayed chromatin recruitment of SASP modulators is the result of non‐canonical DDR signaling that ensures SASP activation only in the context of senescence and not in response to transient DNA damage‐induced proliferation arrest.

中文翻译：

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非规范的 ATM/MRN 活动暂时定义了衰老分泌程序。

衰老细胞表现出衰老相关 (SA) 表型程序，例如稳定增殖停滞 (SAPA) 和分泌表型 (SASP)。衰老诱导的持续性 DNA 双链断裂 (pDSBs) 会导致立即的 DNA 损伤反应 (DDR) 和 SAPA，但 SASP 需要数天才能形成。在这里，我们表明，在直接规范 DDR 之后，ATM 和 MRN 复合物的延迟染色质积累与 SASP 因子的表达相吻合。重要的是，组蛋白去乙酰化酶抑制剂 (HDACi) 在没有 DNA 损伤的情况下触发 SAPA 和 SASP。然而，HDACi 诱导的 SASP 也需要 ATM/MRN 活性并导致它们在染色质上的积累，揭示了 SASP 成熟的基础的 DNA 损伤独立、非规范的 DDR 活性。这种非规范的 DDR 是在染色质上募集转录因子 NF-κB 所必需的，但不是其核易位所必需的。非规范 DDR 进一步不需要 ATM 激酶活性，表明结构 ATM 功能。我们认为 SASP 调节剂的染色质募集延迟是非规范 DDR 信号传导的结果，该信号确保 SASP 仅在衰老的背景下激活，而不是响应瞬时 DNA 损伤诱导的增殖停滞。