As a sensor of cytosolic DNA, the role of cyclic GMP-AMP synthase (cGAS) in innate immune response is well established, yet how its functions in different biological conditions remain to be elucidated. Here, we identify cGAS as an essential regulator in inhibiting mitotic DNA double-strand break (DSB) repair and protecting short telomeres from end-to-end fusion independent of the canonical cGAS-STING pathway. cGAS associates with telomeric/subtelomeric DNA during mitosis when TRF1/TRF2/POT1 are deficient on telomeres. Depletion of cGAS leads to mitotic chromosome end-to-end fusions predominantly occurring between short telomeres. Mechanistically, cGAS interacts with CDK1 and positions them to chromosome ends. Thus, CDK1 inhibits mitotic non-homologous end joining (NHEJ) by blocking the recruitment of RNF8. cGAS-deficient human primary cells are defective in entering replicative senescence and display chromosome end-to-end fusions, genome instability and prolonged growth arrest. Altogether, cGAS safeguards genome stability by controlling mitotic DSB repair to inhibit mitotic chromosome end-to-end fusions, thus facilitating replicative senescence.

作为细胞溶质 DNA 的传感器，环状 GMP-AMP 合酶 (cGAS) 在先天免疫反应中的作用已得到充分证实，但其在不同生物条件下的功能仍有待阐明。在这里，我们将 cGAS 鉴定为抑制有丝分裂 DNA 双链断裂 (DSB) 修复和保护短端粒免于端对端融合的重要调节因子，与经典的 cGAS-STING 途径无关。当 TRF1/TRF2/POT1 缺乏端粒时，cGAS 与有丝分裂期间的端粒/亚端粒 DNA 相关联。cGAS 的消耗导致主要发生在短端粒之间的有丝分裂染色体端到端融合。从机制上讲，cGAS 与 CDK1 相互作用并将它们定位到染色体末端。因此，CDK1 通过阻断 RNF8 的募集来抑制有丝分裂非同源末端连接 (NHEJ)。cGAS 缺陷的人类原代细胞在进入复制性衰老方面存在缺陷，并显示出染色体端到端融合、基因组不稳定性和长期生长停滞。总之，cGAS 通过控制有丝分裂 DSB 修复以抑制有丝分裂染色体端到端融合，从而促进复制性衰老，从而保障基因组稳定性。