Cytoplasmic chromatin triggers inflammation in senescence and cancer

Z Dou, K Ghosh, MG Vizioli, J Zhu, P Sen… - Nature, 2017 - nature.com
Nature, 2017nature.com
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 …
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.
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