Mitotic progression following DNA damage enables pattern recognition within micronuclei
Open accessPublished version of a preprint
Abstract
Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy. A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP-AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)-cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.
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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 [22]
The section labeled Abstract (page not provided) reports that cGAS localizes to micronuclei, and Extended Data Figure 4 describes measuring cGAS-positive micronuclei. However, the passages do not report that approximately half of all micronuclei are cGAS-positive. The reported majority concerns micronucleated daughter cells in a live-imaging experiment, not all micronuclei. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCompelling clinical and experimental evidence support the importance of IFN-β production by tumor cells themselves in mediating antitumor responses to radiation therapy in combination with immune checkpoint inhibitors.
“Nevertheless, compelling clinical and experimental evidence support the importance of IFN-β production by tumor cells themselves in mediating antitumor responses to radiation therapy in combination with immune checkpoint inhibitors46–48.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [46]
The paper’s main text (indexed under Abstract; no page supplied) reports that deleting STING in irradiated B16 tumor cells eliminated the abscopal tumor-growth delay seen with anti-CTLA4, and Extended Data Figure 6 reports impaired radiation-induced inflammatory gene expression in those cells. This supports a role for tumor-cell STING signaling in the combination response, but the copy does not establish that IFN-β production by the tumor cells specifically mediates it. The cited clinical case reports concern abscopal responses, not a demonstrated clinical role for tumor-cell IFN-β. (LLM, conf=0.85)
Experimental — accuracy not yet measuredType 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 [906]
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 [906]
cGAS activation caused by rupture of the MN nuclear envelope is thought to be the main trigger of an interferon-based inflammatory response.
“Similarly, cGAS activation due to rupture of the MN nuclear envelope is thought to be the major trigger of an interferon-based inflammatory response (Bartsch et al., 2017; Gekara, 2017; Harding et al., 2017; Mackenzie et al., 2017).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Harding et al., 2017
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 Harding et al., 2017
Cytoplasmic DNA in early senescent cells can originate from micronuclei produced due to chromosome segregation errors during mitosis.
“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 [175]
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- Authors
- Harding, S. M., Benci, J. L., Irianto, J., Discher, D. E., Minn, A. J., & Greenberg, R. A.
- Affiliations
- University of Pennsylvania (US)
- Parker Institute for Cancer Immunotherapy (US)
- Corresponding author
- Greenberg, Roger A.
- ORCID
- Venue
- Nature
- Published
- 2017-07-31
- Volume
- 548
- Issue
- 7668
- Pages
- 466-470
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5857357
- OpenAlex
- W2733154631
- Cited by
- 1,508
- References
- 34
- Citations by year
- 2026: 143 · 2025: 149 · 2024: 184 · 2023: 198 · 2022: 185 · 2021: 200 · 2020: 195 · 2019: 139 · 2018: 92 · 2017: 20 · 2013: 1
- FWCI
- 55.10
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health (CA17494)
- National Heart, Lung, and Blood Institute (R21HL128187, R01HL124106)
- National Cancer Institute (R01CA138835, U54CA193417, R01CA174904)
- National Institute of General Medical Sciences (R01GM101149)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- micronuclei, mitosis, DNA damage, cGAS, STING, innate immunity, ionizing radiation, interferon signaling, abscopal effect, immune checkpoint blockade, DNA double-strand breaks, tumor microenvironment, cell cycle
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Disease Models, Animal, DNA Damage, Female, Humans, Inflammation, Interferons, Melanoma, Experimental, Membrane Proteins, Mice, Inbred C57BL, Mitosis, Nucleotidyltransferases, Signal Transduction, Cell Line, Tumor, Micronuclei, Chromosome-Defective, Receptors, Pattern Recognition, Mice, DNA Breaks, Double-Stranded, Cell Cycle Checkpoints, CTLA-4 Antigen
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