The cGAS–STING Pathway Influences Taxane Response Free

Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytoplasmic DNA sensor that triggers inflammation via the cGAS–stimulator of interferon genes (STING) pathway. During mitosis, nuclear envelope breakdown could bring cGAS into contact with nuclear DNA, and Zierhut and colleagues found that cGAS has greater affinity for nucleosomes than for DNA in vitro and that binding of DNA and nucleosomes appeared not to occur at the same sites. Although nucleosomes stimulated cGAMP synthesis by cGAS, the catalytic rate was lower than the rate produced by DNA binding. Live imaging of fluorescently tagged cGAS revealed that cGAS associates with chromosomes immediately after nuclear envelope breakdown in mitosis; however, activation of the cGAS–STING pathway (as measured by phosphorylation of IRF3 at Ser396) was delayed on the order of hours. Thus, chromosome binding by cGAS may not have consequences during normal mitosis, which is complete in approximately 30 minutes, but may be relevant during mitotic arrest such as that caused by treatment with taxanes (e.g., paclitaxel). Supporting this, three cGAS-negative breast cancer cell lines were not killed during mitotic arrest caused by paclitaxel, whereas three of four tested cGAS-positive breast cancer cell lines did die during mitosis. In HeLa cells and a fibroblast cell line, cGAS depletion extended mitotic lifespan after paclitaxel treatment. cGAS-mediated cell death in HeLa cells occurred by accelerating apoptosis, and the mechanism appeared to involve suppression of the activity of the antiapoptotic protein BCL-xL, leading to promotion of mitochondrial outer membrane permeabilization, an apoptosis trigger. Typically, cGAS activation and the resulting cGAMP production stimulates the production of transcription factors such as IRF3; however, this was not the case during mitosis in a fibroblast cell line, showing that the cGAS-mediated cell death during mitosis proceeds via a different mechanism. Demonstrating the potential clinical relevance, cGAS increased paclitaxel tumor response in a mouse xenograft cancer model, and there was a correlation between prolonged patient survival and high cGAS expression in data from patients with lung and ovarian cancers.

Zierhut C, Yamaguchi N, Paredes M, Luo J, Carroll T, Funabiki H. The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell 2019;178:302–15.

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