cGAS is essential for cellular senescence

Abstract

Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.ellular senescence is a state of irreversible cell cycle arrest triggered by various types of cellular and environmental stress, such as telomere shortening, oncogene activation, and DNA damage (1, 2). Senescence appears to be an antiproliferation process that limits the growth of damaged cells and acts as a potent barrier to tumorigenesis (3, 4). Senescence is characterized by several unique features, including enlarged and flattened cell morphology (5), increased senescence-associated β-galactosidase (SA-β-Gal) activity (6, 7), and in some cell types, a widespread change in chromatin modification, known as senescence-associated heterochromatin foci (SAHF) (7). At the molecular level, the p53-p21 WAF1 and pRb-p16 INK4a tumor suppressor pathways have been reported to be key mechanisms that control the execution and maintenance of senescence (8,9). In addition to these cellular features, senescent cells also undergo massive changes in the expression of genes that are thought to affect the tissue microenvironment (5). Senescent cells secrete a variety of soluble factors including inflammatory cytokines, growth factors, and proteases; such senescence-associated secretory phenotype (SASP) is a hallmark of senescence (10-12).Components of SASP not only serve as a marker of senescence, but also participate in the senescence process (13). Interleukin 6 (IL6) and IL8, two key components of SASP, reinforce the senescence growth arrest in neighboring cells (14,15). Additionally, these cytokines and other secreted factors attract immune cells, leading to the elimination of senescent cells (16). Given these important functions, SASP is regulated at both transcriptional and epigenetic levels, such as by nuclear factor κB (NF...

Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING

“…We thus infected the reconstituted MEFs with herpes simplex virus 1 (HSV-1, a DNA virus) or vesicular stomatitis virus (VSV, an RNA virus) and indeed noted that cells expressing the STING variants were resistant to viral replication (Figure 2F). Of interest is that it has recently been reported that the STING pathway can influence cellular senescence, a cell-autonomous growth arrest program, by inducing senescence-associated secretory phenotype (SASP) factors such as IL-6 (Dou et al, 2017; Gl€uck et al, 2017; Yanget al, 2017). Because we had observed that STING (R284S) can induce IL-6, we evaluated whether this variant can influence SASP (Figure 2D).…”

Chromosomal instability drives metastasis through a cytosolic DNA response

“…Consequently, suppressing CIN reduces metastasis even in highly aneuploid cells. The repercussions of STING activation are context-dependent and range from senescence to tumorigenesis 21,27,28,30 . Given that chromosomally unstable cells are awash with cytosolic DNA, we raise the interesting possibility that by suppressing downstream type I interferon signaling 30 and instead upregulating the alternative NF-κB pathway, they have substituted a lethal epithelial response to inflammation with that of myeloid-derived cells 36,37 , thereby engaging in some form of immune mimicry.…”

“…In chromosomally stable cells, cytosolic dsDNA is scarce and is sensed by the cGAS-STING pathway 19 , leading to induction of type I interferon stimulated genes (ISGs) 22,23,27 . Indeed, induced missegregation of the Y chromosome led to the upregulation of OAS2, an ISG, and increased interferon-β production by DLD-1 cells (Extended Data Fig.…”

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

“…TREX1 is an important regulator of the intrinsic process, as it is up-regulated at high doses of radiation and drives attenuation of the immunogenic signal. Recently, five independent studies have shed new insight into the role of the cGAS–STING axis in maintenance of genomic integrity by intrinsic sensing of genotoxic stress [34 •• ,59 •• ,60 •• ,61 •• ,62 •• ]. In cells deficient in ribonuclease RNase H2, a causative factor in inflammatory AGS that is involved in DNA synthesis and repair [30–33,34 •• ], cGAS specifically localizes to micronuclei, which are formed from mis-segregation of chromosomal DNA, where it initiates an inflammatory response [34 •• ].…”