The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • DNA / metabolism*
  • Female
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mitosis
  • Neoplasms / drug therapy
  • Neoplasms / mortality
  • Neoplasms / pathology
  • Nucleosomes / metabolism
  • Nucleotidyltransferases / antagonists & inhibitors
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / metabolism*
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / isolation & purification
  • Signal Transduction
  • Survival Rate
  • Transcriptional Activation
  • bcl-X Protein / metabolism

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Nucleosomes
  • RNA, Small Interfering
  • Recombinant Proteins
  • bcl-X Protein
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, human
  • Paclitaxel