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Updated: Jan 22, 2026
11:44
Stimulation of Cytoplasmic DNA Sensing Pathways In Vitro and In Vivo
Published on: September 18, 2014
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The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death
Christian Zierhut1, Norihiro Yamaguchi2, Maria Paredes1
1Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
Cell
|July 13, 2019
Summary
Nucleosomes inhibit the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway during mitosis. Aberrant mitosis triggers cGAS-STING-dependent IRF3 phosphorylation, inducing apoptosis and enhancing anti-cancer drug response.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Cytoplasmic DNA sensing via the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway typically induces inflammation.
- The role of cGAS-STING activation by chromosomal DNA during mitosis remains unclear.
- Nucleosomes are known regulators of DNA accessibility and cellular processes.
Purpose of the Study:
- To investigate the functional consequences of exposing cGAS to chromosomal DNA during mitosis.
- To determine if the cGAS-STING pathway is activated during normal or aberrant mitosis.
- To explore the potential of targeting the cGAS-STING pathway in cancer therapy.
Main Methods:
- Assessing cGAS-STING pathway activation during mitosis using biochemical assays.
- Investigating the role of nucleosomes in inhibiting cGAS activity.
- Analyzing IRF3 phosphorylation and its downstream effects on apoptosis.
- Evaluating the impact of cGAS and IRF3 expression on tumor response to anti-mitotic agents in preclinical models and patient data.
Main Results:
- Nucleosomes competitively inhibit DNA-dependent cGAS activation, preventing effective cGAS-STING pathway activation during normal mitosis.
- Mitotic arrest leads to slow accumulation of cGAS-dependent IRF3 phosphorylation without inflammation.
- Phosphorylated IRF3 induces apoptosis independently of its DNA-binding domain by promoting mitochondrial outer membrane permeabilization.
- Expression of cGAS and IRF3 enhances the responsiveness of cancer cells and xenograft tumors to anti-mitotic drugs like Taxol.
- TCGA data suggests a correlation between cGAS expression and taxane response in non-small cell lung cancer.
Conclusions:
- The cGAS-STING pathway is actively suppressed by nucleosomes during normal mitosis.
- Accumulated phosphorylated IRF3 during mitotic aberrations triggers transcription-independent apoptosis.
- The cGAS-STING pathway, when expressed in cancer cells, can sensitize tumors to anti-mitotic therapies, offering a potential therapeutic strategy.
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