Mitotic progression following DNA damage enables pattern recognition within micronuclei

By S. Harding, Joseph L. Benci, J. Irianto, Dennis E. Discher, Andy J. Minn, R. Greenberg. Nature, 2017

1,340 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/18c699a1ca92060a01f238a8f0665064c353f8e2

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Citations in the corpus

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).”
Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11 (2019, background): “More recently, cGAS–STING sensing of cytoplasmic DNA and micronuclei following radiation has emerged as an important connection between innate immunity and radiotherapy (3, 4, 32).”
DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer (2020, background): “Harding et al.(429) revealed that cell cycle progression through mitosis following DSBs leads to the formation of micronuclei.”
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].”