Cytoplasmic chromatin triggers inflammation in senescence and cancer

Dou, Z. et al. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature, 550(7676), pp. 402-406. (doi: 10.1038/nature24050) (PMID:28976970) (PMCID:PMC5850938)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vizioli, Dr Maria Grazia and Adams, Professor Peter
• Authors: 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., Ahasan Al Tanim, K.M., Barber, G. N., Seykora, J. T., Millar, S. E., Kaestner, K. H., Garcia, B. A., Adams, P. D., and Berger, S. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature
• Publisher: Nature Publishing Group
• ISSN: 0028-0836
• ISSN (Online): 1476-4687
• Published Online: 04 October 2017
• Copyright Holders: Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
• First Published: First published in Nature 550(7676): 402-406
• Publisher Policy: Reproduced in accordance with the publisher copyright policy