ATR responds to mechanical stress at the nuclear envelope and mediates envelope-associated repair of aberrant topological DNA states. By combining microscopy, electron microscopic analysis, biophysical and in vivo models, we report that ATR-defective cells exhibit altered nuclear plasticity and YAP delocalization. When subjected to mechanical stress or undergoing interstitial migration, ATR-defective nuclei collapse accumulating nuclear envelope ruptures and perinuclear cGAS, which indicate loss of nuclear envelope integrity, and aberrant perinuclear chromatin status. ATR-defective cells also are defective in neuronal migration during development and in metastatic dissemination from circulating tumor cells. Our findings indicate that ATR ensures mechanical coupling of the cytoskeleton to the nuclear envelope and accompanying regulation of envelope-chromosome association. Thus the repertoire of ATR-regulated biological processes extends well beyond its canonical role in triggering biochemical implementation of the DNA damage response.

ATR 对核包膜处的机械应力作出反应，并介导异常拓扑 DNA 状态的包膜相关修复。通过结合显微镜、电子显微镜分析、生物物理和体内模型，我们报告了 ATR 缺陷细胞表现出改变的核可塑性和 YAP 离域。当受到机械应力或经历间质迁移时，ATR 缺陷核塌陷，累积核膜破裂和核周 cGAS，这表明核膜完整性丧失和核周染色质状态异常。ATR 缺陷细胞在发育过程中的神经元迁移和循环肿瘤细胞的转移传播中也存在缺陷。我们的研究结果表明，ATR 确保细胞骨架与核包膜的机械耦合以及伴随的包膜-染色体结合调节。因此，ATR 调节的生物过程的全部范围远远超出了其在触发 DNA 损伤反应的生化实施方面的典型作用。