Journal
NATURE CELL BIOLOGY
Volume 19, Issue 9, Pages 1061-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3586
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Funding
- SNF [BSSGI0-155984, 31003A_159836]
- Gebert Ruf Foundation [GRS-059_14]
- Else Kroner-Fresenius Stiftung [2014_A250]
- German Research Foundation (DFG) [FOR2314, SFB685]
- Gottfried Wilhelm Leibniz Program
- European Research Council
- German Ministry for Education and Research (BMBF) (eMed (Multiscale HCC))
- German Universities Excellence Initiative
- German Center for Translational Cancer Research (DKTK)
- German-Israeli Cooperation in Cancer Research (DKFZ-MOST)
- long-term EMBO fellowship [ALTF 203-2016]
- UK Medical Research Council [MRC core funding of the MRC Human Immunology Unit]
- Wellcome Trust [100954]
- Medical Research Council [MC_UU_00008/8, MC_UU_12010/8] Funding Source: researchfish
- Wellcome Trust [100954/Z/13/Z] Funding Source: researchfish
- Swiss National Science Foundation (SNF) [31003A_159836] Funding Source: Swiss National Science Foundation (SNF)
- MRC [MC_UU_00008/8, MC_UU_12010/8] Funding Source: UKRI
- Wellcome Trust [100954/Z/13/Z] Funding Source: Wellcome Trust
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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.
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