Flynn Patrick J, Koch Peter D, Mitchison Timothy J
Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114.
Proc Natl Acad Sci U S A. 2021 Nov 30;118(48). doi: 10.1073/pnas.2103585118.
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 2'3'-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.
有丝分裂错误可激活环鸟苷酸-腺苷酸合成酶（cGAS）并诱导I型干扰素（IFN）信号传导。目前的模型认为，染色体分离错误会产生微核，微核破裂会激活cGAS。我们使用了一组抗有丝分裂药物来干扰人类成纤维细胞的有丝分裂，并在随后的间期测量了异常的核形态、cGAS定位和IFN信号传导。微核始终募集cGAS但不激活它。相反，IFN信号传导与cGAS包被的染色质桥的形成相关，这些染色质桥是由微管稳定剂和MPS1抑制剂选择性产生的。阻止胞质分裂的药物可抑制染色质桥对cGAS的激活。我们通过测量2'3'-cGAMP向成纤维细胞的旁分泌转移，在无法分泌IFN的癌细胞系和小鼠细胞中证实了染色质桥对cGAS的激活。我们提出，当cGAS在染色质桥中被拉伸时，它会被自身染色质选择性激活。对有丝分裂失败的细胞的免疫监视以及紫杉烷和MPS1抑制剂的抗肿瘤作用可能取决于这种效应。
