The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
cGAS surveillance of micronuclei links genome instability to innate immunity
Open accessAbstract
DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.
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“Besides the exogenous dsDNA released by virus or bacterial, intrinsic self-dsDNA released into the cytosol from nucleus or mitochondrion due to cellular or mitochondrial stress can also bind to cGAS and activate cGAS-STING pathway.400,401”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [400]
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 found a striking localization of cGAS to approximately half of all micronuclei as previously observed22,23.”
From Chromosomal instability drives metastasis through a cytosolic DNA response (2018) · cites this paper as [23]
Experimental — accuracy not yet measuredIn the citing paper
“Type I IFN is produced by cancer cells succumbing to ICD by a mechanism involving the detection of endogenous dsRNA by TLR3 [873], or double-stranded DNA (dsDNA) by cGAS [854, 905, 906].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [905]
In the citing paper
“Moreover, recent data indicate that cancer cells escaping mitotic catastrophe efficiently promote the secretion of type I IFN following the detection of cytosolic dsDNA by cGAS, potentially resulting in their elimination by immunological mechanisms [905, 906].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [905]
In the citing paper
“this strategy may also impair signaling of MN-initiated cell-intrinsic immune surveillance and tumor suppression (Harding et al., 2017; Mackenzie et al., 2017)”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Mackenzie et al., 2017
In the citing paper
“Mechanistically, cytoplasmic DNA in early senescent cells can originate from micronuclei produced due to chromosome segregation errors during mitosis [175,176].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [176]
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“Besides the exogenous dsDNA released by virus or bacterial, intrinsic self-dsDNA released into the cytosol from nucleus or mitochondrion due to cellular or mitochondrial stress can also bind to cGAS and activate cGASSTING pathway.(400,401) Binding with long dsDNA has been shown to induce the rearrangement of cGAS to f…”
BackgroundChromosomal instability drives metastasis through a cytosolic DNA response
Bakhoum, S. F., Ngo, B., Laughney, A. M., Cavallo, J.-A., Murphy, C. J., Ly, P., Shah, P., Sriram, R. K., Watkins, T. B. K., Taunk, N. K., et al. (2018) · Nature · doi:10.1038/nature25432 · Cited by 1,593
Metadata
- Authors
- Mackenzie, K. J., Carroll, P., Martin, C.-A., Murina, O., Fluteau, A., Simpson, D. J., Olova, N., Sutcliffe, H., Rainger, J. K., Leitch, A., Osborn, R. T., Wheeler, A. P., Nowotny, M., Gilbert, N., Chandra, T., Reijns, M. A. M., & Jackson, A. P.
- Affiliations
- Institute of Genetics and Cancer (GB)
- International Institute of Molecular and Cell Biology (PL)
- Corresponding author
- Reijns, Martin A. M.
- Jackson, Andrew P.
- ORCID
- Venue
- Nature
- Published
- 2017-07-24
- Volume
- 548
- Issue
- 7668
- Pages
- 461-465
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5870830
- OpenAlex
- W2738136165
- Cited by
- 1,752
- References
- 56
- Citations by year
- 2026: 208 · 2025: 196 · 2024: 225 · 2023: 233 · 2022: 216 · 2021: 231 · 2020: 193 · 2019: 125 · 2018: 99 · 2017: 26
- FWCI
- 54.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (158709)
- Medical Research Council (1805075, MR/K01563X/1, MC_PC_15075)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- cGAS, micronuclei, genomic instability, innate immunity, cytosolic DNA sensing, autoinflammation, chromothripsis, DNA damage, interferon-stimulated genes, cancer, mitosis, lagging chromosomes, immunostimulatory DNA
- MeSH terms
- Chromothripsis, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Cell Cycle, Chromatin, Cytoplasm, DNA, DNA Damage, Female, Humans, Immunity, Innate, Inflammation, Lasers, Male, Mitosis, Nuclear Envelope, Nucleotidyltransferases, Microdissection, Genomic Instability, Cell Line, Tumor, Micronuclei, Chromosome-Defective, Mice, Single-Cell Analysis, Transcriptome
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