Cellular senescence is a response to many stressful insults. DNA damage is a consistent feature of senescent cells, but in many cases its source remains unknown. Here, we identify the cellular endonuclease caspase-activated DNase (CAD) as a critical factor in the initiation of senescence. During apoptosis, CAD is activated by caspases and cleaves the genomic DNA of the dying cell. The CAD DNase is also activated by sub-lethal signals in the apoptotic pathway, causing DNA damage in the absence of cell death. We show that sub-lethal signals in the mitochondrial apoptotic pathway induce CAD-dependent senescence. Inducers of cellular senescence, such as oncogenic RAS, type-I interferon, and doxorubicin treatment, also depend on CAD presence for senescence induction. By directly activating CAD experimentally, we demonstrate that its activity is sufficient to induce senescence in human cells. We further investigate the contribution of CAD to senescence in vivo and find substantially reduced signs of senescence in organs of ageing CAD-deficient mice. Our results show that CAD-induced DNA damage in response to various stimuli is an essential contributor to cellular senescence.

中文翻译：

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Caspase 激活的 DNase 促进细胞衰老。


细胞衰老是对许多应激损伤的反应。 DNA 损伤是衰老细胞的一贯特征，但在许多情况下其来源仍然未知。在这里，我们确定细胞内切核酸酶半胱天冬酶激活的 DNase (CAD) 是衰老起始的关键因素。在细胞凋亡过程中，CAD 被半胱天冬酶激活并切割垂死细胞的基因组 DNA。 CAD DNase 也会被细胞凋亡途径中的亚致死信号激活，在没有细胞死亡的情况下造成 DNA 损伤。我们发现线粒体凋亡途径中的亚致死信号会诱导 CAD 依赖性衰老。细胞衰老诱导剂，例如致癌 RAS、I 型干扰素和阿霉素治疗，也依赖于 CAD 的存在来诱导衰老。通过实验直接激活 CAD，我们证明其活性足以诱导人体细胞衰老。我们进一步研究了 CAD 对体内衰老的影响，发现 CAD 缺陷小鼠的器官衰老迹象显着减少。我们的研究结果表明，CAD 因各种刺激而引起的 DNA 损伤是细胞衰老的重要因素。