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Cytoplasmic chromatin triggers inflammation in senescence and cancer
Open accessAbstract
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.
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“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).”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [60]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [39]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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.”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [60]
The cited source says what the claim attributes to it.
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”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [68]
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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.”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [68]
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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).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Dou et al. 2017
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In the citing paper
“Previous research has revealed DNA damage products5–7 and retroelement amplification52 as upstream triggers of cGAS in senescence.”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [7]
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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.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [22]
Experimental — accuracy not yet measuredIn 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.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Dou et al., 2017
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).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Dou et al., 2017
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).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Dou 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”
From COVID-19 and cellular senescence (2023) · cites this paper as [55]
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).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2017
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).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as 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)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2017
In the citing paper
“although MN-dependent cGAS activation of interferon genes is well documented in cancer cells”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2017
In the citing paper
“CCF activation of cGAS in senescent cells is typically associated with an NF-κB-dependent cytokine response”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Dou et al., 2017
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].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [171]
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].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [171]
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].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [171]
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].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [171]
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].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [171]
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Metadata
- Authors
- Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., Capell, B. C., Xu, C., Xu, M., Kieckhaefer, J. E., Jiang, T., Shoshkes-Carmel, M., Tanim, K. M. A. A., Barber, G. N., Seykora, J. T., Millar, S. E., Kaestner, K. H., Garcia, B. A., Adams, P. D., & Berger, S. L.
- Affiliations
- University of Pennsylvania (US)
- Cancer Research UK Scotland Institute (GB)
- Peking University (CN)
- Abramson Cancer Center (US)
- University of Miami (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Adams, Peter D.
- Berger, Shelley L.
- ORCID
- Venue
- Nature
- Published
- 2017-10
- Volume
- 550
- Issue
- 7676
- Pages
- 402-406
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5850938
- OpenAlex
- W2762611634
- Cited by
- 1,335
- References
- 37
- Citations by year
- 2026: 177 · 2025: 157 · 2024: 184 · 2023: 156 · 2022: 174 · 2021: 158 · 2020: 127 · 2019: 115 · 2018: 75 · 2017: 10
- FWCI
- 40.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (CA078831)
- National Institute on Aging (K99AG053406, P01AG031862)
- National Cancer Institute (P01CA196539, R01CA078831)
- National Institute of Allergy and Infectious Diseases (R01AI079336)
- National Institute of Diabetes and Digestive and Kidney Diseases (K08DK106478)
- National Institute of Environmental Health Sciences (P30ES013508)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08AR070289, P30AR069589, T32AR007465)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- cGAS-STING pathway, cytosolic DNA sensing, cellular senescence, senescence-associated secretory phenotype, chronic inflammation, tumor surveillance, oncogenic Ras, ionizing radiation, innate immunity, tumor inflammation
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Chromatin, Cytoplasm, Female, Humans, Immunity, Innate, Inflammation, Liver, Male, Membrane Proteins, Neoplasms, Nucleotidyltransferases, Radiation, Ionizing, Oncogene Protein p21(ras), Cytokines, Cellular Senescence, Cell Line, Tumor, Mice
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