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Cellular senescence is triggered by various distinct stresses and characterized by a permanent cell cycle arrest. Senescent cells secrete a variety of inflammatory factors, collectively referred to as the senescence-associated secretory phenotype (SASP). The mechanism(s) underlying the regulation of the SASP remains incompletely understood. Here we define a role for innate DNA sensing in the regulation of senescence and the SASP. We find that cyclic GMP-AMP synthase (cGAS) recognizes cytosolic chromatin fragments in senescent cells. The activation of cGAS, in turn, triggers the production of SASP factors via stimulator of interferon genes (STING), thereby promoting paracrine senescence. We demonstrate that diverse stimuli of cellular senescence engage the cGAS-STING pathway in vitro and we show cGAS-dependent regulation of senescence following irradiation and oncogene activation in vivo. Our findings provide insights into the mechanisms underlying cellular senescence by establishing the cGAS-STING pathway as a crucial regulator of senescence and the SASP.

Original publication

DOI

10.1038/ncb3586

Type

Journal article

Journal

Nat Cell Biol

Publication Date

09/2017

Volume

19

Pages

1061 - 1070

Keywords

Animals, Cell Aging, Cell Proliferation, Cells, Cultured, Chromatin, Cytosol, Enzyme Activation, Female, Genotype, Immunity, Innate, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Knockout, Nucleotidyltransferases, Oxidative Stress, Paracrine Communication, Phenotype, RNA Interference, Signal Transduction, Time Factors, Transfection