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Cell. 2019 Jul 11;178(2):302-315.e23. doi: 10.1016/j.cell.2019.05.035.

The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death.

Author information

1
Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: czierhut@rockefeller.edu.
2
Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY 10065, USA.
3
Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA.
4
Bioinformatics Resource Center, The Rockefeller University, New York, NY 10065, USA.
5
Laboratory of Chromosome and Cell Biology, The Rockefeller University, New York, NY 10065, USA. Electronic address: funabih@rockefeller.edu.

Abstract

Pathogenic and other cytoplasmic DNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce inflammation via transcriptional activation by IRF3 and nuclear factor κB (NF-κB), but the functional consequences of exposing cGAS to chromosomes upon mitotic nuclear envelope breakdown are unknown. Here, we show that nucleosomes competitively inhibit DNA-dependent cGAS activation and that the cGAS-STING pathway is not effectively activated during normal mitosis. However, during mitotic arrest, low level cGAS-dependent IRF3 phosphorylation slowly accumulates without triggering inflammation. Phosphorylated IRF3, independently of its DNA-binding domain, stimulates apoptosis through alleviating Bcl-xL-dependent suppression of mitochondrial outer membrane permeabilization. We propose that slow accumulation of phosphorylated IRF3, normally not sufficient for inducing inflammation, can trigger transcription-independent induction of apoptosis upon mitotic aberrations. Accordingly, expression of cGAS and IRF3 in cancer cells makes mouse xenograft tumors responsive to the anti-mitotic agent Taxol. The Cancer Genome Atlas (TCGA) datasets for non-small cell lung cancer patients also suggest an effect of cGAS expression on taxane response.

KEYWORDS:

cGAS; cancer; cell death; innate immunity; mitosis; paclitaxel; taxane

PMID:
31299200
PMCID:
PMC6693521
[Available on 2020-07-11]
DOI:
10.1016/j.cell.2019.05.035

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