cGAS surveillance of micronuclei links genome instability to innate immunity

Mackenzie, Karen J.; Carroll, Paula; Martin, Carol-Anne; Murina, Olga; Fluteau, Adeline; Simpson, Daniel J.; Olova, Nelly; Sutcliffe, Hannah; Rainger, Jacqueline K.; Leitch, Andrea; Osborn, Ruby T.; Wheeler, Ann P.; Nowotny, Marcin; Gilbert, Nick; Chandra, Tamir; Reijns, Martin A. M.; Jackson, Andrew P.

doi:10.1038/nature23449

Cited by 1,752interferon and immune responsesImmune Response and InflammationDNA Repair Mechanisms

cGAS surveillance of micronuclei links genome instability to innate immunity

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Mackenzie, Karen J., Carroll, Paula, Martin, Carol-Anne, Murina, Olga, Fluteau, Adeline, Simpson, Daniel J., Olova, Nelly, Sutcliffe, Hannah +9 more·2017·Nature

DOI 10.1038/nature23449PMC PMC5870830

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Abstract

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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Intrinsic self-dsDNA released into the cytosol from nucleus or mitochondrion due to cellular or mitochondrial stress can bind to cGAS and activate the cGAS-STING pathway.
“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]
The paper’s Abstract reports that breakdown of micronuclear envelopes exposes nuclear self-DNA to cGAS, which activates signaling through STING. It notes that mitochondrial DNA is normally compartmentalized, but does not establish that mitochondrial stress releases it into the cytosol or activates this pathway. (LLM, conf=0.88)
Experimental — accuracy not yet measured
cGAS localizes to approximately half of all micronuclei.
“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]
The paper reports that cGAS localizes to micronuclei, but its quantified result is 83.3 ± 1.4% GFP-cGAS-positive micronuclei in RNase H2-deficient mouse fibroblasts (Abstract, Fig. 1d), not approximately half. It also describes localization in other settings without establishing a proportion for all micronuclei. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Type I IFN is produced by cancer cells undergoing ICD via TLR3 detection of endogenous dsRNA or cGAS detection of dsDNA.
“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]
Cancer cells escaping mitotic catastrophe promote type I IFN secretion after cGAS detection of cytosolic dsDNA, potentially leading to immune elimination.
“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]
Such inhibition could also weaken immune surveillance and tumor suppression that begin with MN.
“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

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“micronuclei formation after radiotherapy and chemotherapies leading to cGAS-STING signaling pathway-dependent inflammatory responses in tumors (Harding et al., 2017; Mackenzie et al., 2017).”
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The autophagic network and cancer
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cGAS Conducts Micronuclei DNA Surveillance
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A microscopy reporter for cGAMP reveals rare cGAS activation following DNA damage, and a lack of correlation with micronuclear cGAS enrichmentPreprint
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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: Mackenzie, Karen J.
Martin, Carol-Anne
Murina, Olga
Simpson, Daniel J.
Olova, Nelly
Osborn, Ruby T.
Wheeler, Ann P.
Nowotny, Marcin
Gilbert, Nick
Chandra, Tamir
Reijns, Martin A. M.
Jackson, Andrew P.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-07-24
Volume: 548
Issue: 7668
Pages: 461-465
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature23449
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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cGAS surveillance of micronuclei links genome instability to innate immunity

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