Unknown

Dataset Information

0

Cytoplasmic chromatin triggers inflammation in senescence and cancer.


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.

SUBMITTER: Dou Z 

PROVIDER: S-EPMC5850938 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

altmetric image

Publications


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-ST  ...[more]

Similar Datasets

| S-EPMC7050483 | biostudies-literature
| S-EPMC6333431 | biostudies-literature
| S-EPMC10042704 | biostudies-literature
| S-EPMC5626631 | biostudies-literature
| S-EPMC4001548 | biostudies-literature
| S-EPMC5979529 | biostudies-literature
| S-EPMC7701500 | biostudies-literature
| S-EPMC2230684 | biostudies-literature
| S-EPMC4905342 | biostudies-other
| S-EPMC3704985 | biostudies-literature