Cytoplasmic chromatin triggers inflammation in senescence and cancer

Zhixun Dou, Kanad Ghosh, Maria Grazia Vizioli, Jiajun Zhu, Payel Sen, Kirk J. Wangensteen, Johayra Simithy, Yemin Lan, Yanping Lin, Zhuo Zhou, Brian C. Capell, Caiyue Xu, Mingang Xu, Julia E. Kieckhaefer, Tianying Jiang, Michal Shoshkes-Carmel, K. M.Ahasan Al Tanim, Glen N. Barber, John T. Seykora, Sarah E. MillarKlaus H. Kaestner, Benjamin A. Garcia, Peter D. Adams, Shelley L. Berger

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212 Scopus citations

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.

Original languageEnglish (US)
Article number24050
JournalNature
Volume550
Issue number7676
DOIs
StatePublished - Oct 19 2017

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    Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., Capell, B. C., Xu, C., Xu, M., Kieckhaefer, J. E., Jiang, T., Shoshkes-Carmel, M., Al Tanim, K. M. A., Barber, G. N., Seykora, J. T., ... Berger, S. L. (2017). Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature, 550(7676), [24050]. https://doi.org/10.1038/nature24050