Cytoplasmic chromatin triggers inflammation in senescence and cancer

In the citing paper

“The DNA sensor cGAS and the adaptor protein STING have been reported to be major regulators of the SASP programme across species, presumably by activating NF-κB and the interferon response factor IRF3 (REFS60,112,113).”

In the citing paper

“Cellular senescence is accompanied by substantial reorganization of the nuclear envelope and a breakdown in nucleocytoplasmic trafficking, including altered expression and degradation of Lamin B1, and the formation of cytoplasmic chromatin fragments (CCFs) [38–45].”

In the citing paper

“We and others have previously described a role of the cGAS–STING pathway in the regulation of cellular senescence—a hallmark of ageing5–8.”

In the citing paper

“Loss of nuclear lamina can lead to the release of cytosolic chromatin fragments (CCFs) in the cytoplasm of senescent cells58–60”

In the citing paper

“Downregulation of Lamin B1 leads to collapse of the nuclear envelope, which can trigger release of chromatin fragments from the nucleus to the cytosol, termed cytoplasmic chromatin fragments (CCF).68”

In the citing paper

“However, Dou et al68 demonstrated that inhibiting the cGAS‐STING signaling pathway impaired the immuno‐surveillance of senescent hepatocytes and premalignant hepatocytes, resulting in tumorigenesis in the liver.”

In the citing paper

“The cGAS/STING pathway is considered a key regulator of SASP induction (Dou et al. 2017; Glück et al. 2017; Yang et al. 2017).”

In the citing paper

“Previous research has revealed DNA damage products5–7 and retroelement amplification52 as upstream triggers of cGAS in senescence.”

In the citing paper

“Telomeric DNA damage is more senescence-specific and can be quantified by combining fluorescence in situ hybridization (FISH) for telomeric sequences and immunostaining (immunoFISH) for DSB-associated proteins22.”

In the citing paper

“The mechanisms implicated in the accumulation of cytoplasmic DNA in senescent cells include compromised nuclear integrity due to loss of the nuclear lamina protein, Lamin B1 (Dou et al., 2017) and downregulation of cytoplasmic DNAases such as DNAase 2 and TREX1 (Takahashi et al., 2018) frequently observed in senescent cells.”

In the citing paper

“Recent studies have revealed that cytoplasmic chromatin fragments and transposable elements can stimulate cyclic GMP–AMP synthase linked to stimulator of interferon genes (cGAS-STING) pathway and regulate SASP both in vitro and in vivo where senescence was induced by different stimuli (Dou et al., 2017; Glück et al., 2017; Yang et al., 2017; Li and Chen, 2018).”

In the citing paper

“Loss of cGAS compromised senescence due to reduced SASP in different in vivo models and also accelerated the spontaneous immortalisation of mouse embryonic fibroblasts thereby highlighting the crucial role of the cGAS/STING pathway in tumor suppression due to immune-mediated clearance of premalignant cells (Dou et al., 2017; Glück et al., 2017; Umbreit and Pellman, 2017; Yang et al., 2017).”

In the citing paper

“Senescence-associated DNA damage is sensed via the cGAS–STING pathway, which activates the transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, thereby inducing an interferon and SASP response55–58”

In the citing paper

“Once CCF enter the cytoplasm, they are sensed by the cGAS-STING pathway (Dou et al., 2017; Gluck et al., 2017; Takahashi et al., 2018; Yang et al., 2017) (Fig. 2).”

In the citing paper

“cGAS-STING activation leads to NF-κB activation of SASP genes downstream of STING instead of an interferon gene program, potentially due to p38-MAPK repression of interferon genes in senescent cells (Dou et al., 2017).”

In the citing paper

“a phenotype which is thought to be partly dependent on p38-MAPK activation in senescent cells (Dou et al., 2017)”

In the citing paper

“although MN-dependent cGAS activation of interferon genes is well documented in cancer cells”

In the citing paper

“CCF activation of cGAS in senescent cells is typically associated with an NF-κB-dependent cytokine response”

In the citing paper

“cGAS catalyzes the production of the second messenger cGMP that binds to stimulator of interferon genes (STING). This results in the phosphorylation of both interferon-regulatory factor 3 (IRF3) and of NF-κB transcription factors, thereby stimulating respectively the production of type I interferons and inflammatory cytokines [171,172,173,174].”

In the citing paper

“The nuclear envelope of these micronuclei is unstable and can rupture, leading to the exposure of micronuclear DNA that induces a cellular immune response via cGAS [171,172,173].”

In the citing paper

“Consistently, loss of cGAS and/or STING function reduces SASP factor levels in primary human cells and in mouse models of DNA damage-induced senescence [171,172,173].”

In the citing paper

“Therefore, CCFs formation relies on the constitutive interaction between lamin B1 and LC3, and CCFs formation is required to reinforce OIS by initiating the SASP program [171,172].”

In the citing paper

“Therefore, CCFs formation relies on the constitutive interaction between lamin B1 and LC3, and CCFs formation is required to reinforce OIS by initiating the SASP program [171,172].”