The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death. Academic Article uri icon

Overview

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.

publication date

  • July 11, 2019

Research

keywords

  • Apoptosis
  • DNA
  • Nucleotidyltransferases

Identity

PubMed Central ID

  • PMC6693521

Scopus Document Identifier

  • 85068864186

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2019.05.035

PubMed ID

  • 31299200

Additional Document Info

volume

  • 178

issue

  • 2