Abstract：
:Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear. Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.
journal_name
Naturejournal_title
Natureauthors
Dou Z,Ghosh K,Vizioli MG,Zhu J,Sen P,Wangensteen KJ,Simithy J,Lan Y,Lin Y,Zhou Z,Capell BC,Xu C,Xu M,Kieckhaefer JE,Jiang T,Shoshkes-Carmel M,Tanim KMAA,Barber GN,Seykora JT,Millar SE,Kaestner KH,Garcia BA,Adadoi
10.1038/nature24050subject
Has Abstractpub_date
2017-10-19 00:00:00pages
402-406issue
7676eissn
0028-0836issn
1476-4687pii
nature24050journal_volume
550pub_type
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