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

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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, Rainger, Jacqueline K., Leitch, Andrea, Osborn, Ruby T., Wheeler, Ann P., Nowotny, Marcin, Gilbert, Nick, Chandra, Tamir, Reijns, Martin A. M., Jackson, Andrew P.·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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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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