cGAS is essential for cellular senescence
cGAS is essential for cellular senescence
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DOI：
10.1073/pnas.1705499114
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发表时间：
2017-06-06
影响因子：
11.1
通讯作者：
Chen, Zhijian J.
中科院分区：
文献类型：
--
作者：
Yang, Hui;Wang, Hanze;Chen, Zhijian J.
细胞衰老是肿瘤发生的天然屏障，它有助于几种疗法的抗肿瘤作用，包括放射和化疗药物。衰老在衰老、纤维化和组织修复中也起着重要作用。DNA损伤反应是导致衰老的关键事件，其特征在于包括炎性细胞因子表达的衰老相关分泌表型（SASP）。在这里，我们表明，cGMP-AMP（cGAMP）合酶（cGAS），细胞溶质DNA传感器，激活先天免疫，是必不可少的衰老。cGAS的缺失加速了小鼠胚胎成纤维细胞的自发永生化。cGAS缺失也消除了由自发永生化或DNA损伤剂（包括辐射和依托泊苷）诱导的SASP。CGAS定位于非分裂细胞的细胞质中，但在增殖细胞的有丝分裂期间进入细胞核并与染色质DNA缔合。DNA损伤导致受损DNA在含有cGAS的细胞质病灶中积累。在人肺腺癌患者中，cGAS的低表达与较差的存活率相关。这些结果表明cGAS介导细胞衰老并延缓永生化。这与cGAS在激活抗肿瘤免疫中的作用不同，并且是互补的。
Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.