Details

Autor(en) / Beteiligte

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

Titel

Cytoplasmic chromatin triggers inflammation in senescence and cancer

Ist Teil von

• Nature (London), 2017-10, Vol.550 (7676), p.402-406

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.