The cytoplasmic DNA sensor cGAS promotes mitotic cell death

AbstractThe cyclic GMP-AMP (cGAMP) synthase cGAS counteracts infections by detecting and binding foreign cytoplasmic DNA1. DNA-induced synthesis of cGAMP activates innate immune signalling and apoptosis through the cGAMP receptor STING and the downstream effector IRF31–7. During interphase the nuclear envelope protects chromosomal self-DNA from cGAS, but the consequences of exposing chromosomes to cGAS following mitotic nuclear envelope disassembly are unknown. Here we demonstrate that cGAS associates with chromosomes during mitosis and binds nucleosomes with even higher affinity than naked DNA in vitro. Nucleosomes nevertheless competitively inhibit the DNA-dependent stimulation of cGAS, and accordingly, chromosomal cGAS does not affect mitotic progression under normal conditions. This suggests that nucleosomes prevent the inappropriate activation of cGAS during mitosis by acting as a signature of self-DNA. During prolonged mitotic arrest, however, cGAS becomes activated to promote cell death, limiting the fraction of cells that can survive and escape mitotic arrest induced by the chemotherapeutic drug taxol. Induction of mitotic cell death involves cGAMP synthesis by cGAS, as well as signal transduction to IRF3 by STING. We thus propose that cGAS plays a previously unappreciated role in guarding against mitotic errors, promoting cell death during prolonged mitotic arrest. Our data also indicate that the cGAS pathway, whose activity differs widely among cell lines, impacts cell fate determination upon treatment with taxol and other anti-mitotic drugs. Thus, we propose the innate immune system may be harnessed to selectively target cells with mitotic abnormalities.