ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration.
ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration.
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DOI：
10.1038/s41467-020-18580-9
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发表时间：
2020-09-24
影响因子：
16.6
通讯作者：
Foiani M
中科院分区：
文献类型：
--
作者：
Kidiyoor GR;Li Q;Bastianello G;Bruhn C;Giovannetti I;Mohamood A;Beznoussenko GV;Mironov A;Raab M;Piel M;Restuccia U;Matafora V;Bachi A;Barozzi S;Parazzoli D;Frittoli E;Palamidessi A;Panciera T;Piccolo S;Scita G;Maiuri P;Havas KM;Zhou ZW;Kumar A;Bartek J;Wang ZQ;Foiani M
ATR 对核膜上的机械应力做出反应，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 ATR 缺陷细胞表现出改变的核可塑性和 YAP 离域。当受到机械应力或进行间质迁移时，ATR 缺陷的细胞核塌陷，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扩散方面也存在缺陷。我们的研究结果表明，ATR 确保细胞骨架与核膜的机械耦合以及包膜-染色体关联的伴随调节。因此，ATR 调节的生物过程的全部内容远远超出了其触发 DNA 损伤反应的生化实施的典型作用。细胞核是细胞的机械刚性细胞器，DNA 损伤反应蛋白 ATR 可以在机械应力下定位到核膜。在这里，作者表明 ATR 可能有助于核膜的完整性，并可能在细胞迁移中发挥作用。
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. The nucleus is a mechanically stiff organelle of the cell and the DNA damage response protein ATR can localize to the nuclear envelope upon mechanical stress. Here, the authors show that ATR may contribute to the integrity of the nuclear envelope and may play a role in cell migration.
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影响因子：
21.3
作者：
Gruber, Ralph;Zhou, Zhongwei;Wang, Zhao-Qi
通讯作者：
Wang, Zhao-Qi
影响因子：
9.2
作者：
Isermann, Philipp;Lammerding, Jan
通讯作者：
Lammerding, Jan
影响因子：
64.5
作者：
Bermejo R;Capra T;Jossen R;Colosio A;Frattini C;Carotenuto W;Cocito A;Doksani Y;Klein H;Gómez-González B;Aguilera A;Katou Y;Shirahige K;Foiani M
通讯作者：
Foiani M
影响因子：
4.5
作者：
Hashash N;Johnson AL;Cha RS
通讯作者：
Cha RS
影响因子：
14.9
作者：
Hornbeck PV;Zhang B;Murray B;Kornhauser JM;Latham V;Skrzypek E
通讯作者：
Skrzypek E