Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells

Mitotic errors can activate cyclic GMP-AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 20 30-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.

Automated summary

Mitotic errors can activate cGAS and induce IFN signaling through the formation of chromatin bridges, which are selectively generated by microtubule stabilizers and MPS1 inhibitors. These chromatin bridges activate cGAS and lead to the transfer of 20 30-cGAMP between cells, suggesting a potential mechanism for immunosurveillance of cells that fail mitosis and antitumor actions of taxanes and MPS1 inhibitors.