cGAS surveillance of micronuclei links genome instability to innate immunity

By K. Mackenzie, P. Carroll, Carol-Anne Martin, O. Murina, Adeline Fluteau, Daniel P. Simpson, Nelly N Olova, H. Sutcliffe, J. Rainger, Andrea K Robertson and 7 more. Nature, 2017

1,550 citations recorded by the source corpus.

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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/7a27e7827858a59910ef8c29ec4c28cefa5bd123

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In Immunology

Citations in the corpus

R-loops as cellular regulators and genomic threats (2019, background): “cGAS-STING activation in AGS cells has been directly linked to cytoplasmic DNA in micronuclei and DNA fragments released from stalled replication forks (Coquel et al., 2018; Mackenzie et al., 2017; Ng et al., 2018).”
DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy (2021, background): “Upon binding the cytosolic DNA, cGAS produces the second messenger cGAMP, which in turn activates STING- inflammatory signaling, and leading to regression of abscopal tumors.(388,389) Moreover, a noncanonical cGAS-independent STING activation pathway has also been revealed to be triggered by the DNA”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “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].”
The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer (2018, background): “After DNA damage, cGAS is recruited to micronuclei (Glück et al., 2017; Harding et al., 2017; Mackenzie et al., 2017; Yang et al., 2017).”
cGAS in action: Expanding roles in immunity and inflammation (2019, background): “Following exposure to acute stressors, such as DNA damage inducers, fragile micronuclei are formed, which are prone to rupture unpredictably and cause cGAS activation (66, 67).”
Role of neuroinflammation in neurodegeneration development (2023, background): “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 rearran”