ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration

• Published in: Nature communications Vol. 11; no. 1; pp. 4828 - 16
• Main Authors: Kidiyoor, Gururaj Rao, Li, Qingsen, Bastianello, Giulia, Bruhn, Christopher, Giovannetti, Irene, Mohamood, Adhil, Beznoussenko, Galina V., Mironov, Alexandre, Raab, Matthew, Piel, Matthieu, Restuccia, Umberto, Matafora, Vittoria, Bachi, Angela, Barozzi, Sara, Parazzoli, Dario, Frittoli, Emanuela, Palamidessi, Andrea, Panciera, Tito, Piccolo, Stefano, Scita, Giorgio, Maiuri, Paolo, Havas, Kristina M., Zhou, Zhong-Wei, Kumar, Amit, Bartek, Jiri, Wang, Zhao-Qi, Foiani, Marco
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.09.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/1; 14/19; 14/28; 14/3; 14/33; 14/63; 38/62; 38/89; 631/80/386/1700; 631/80/84/2336; 631/80/86/2371; Actin Cytoskeleton; Animals; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Brain; Cell Nucleus - metabolism; Chromatin; Cytoplasm; Cytoskeleton - metabolism; DNA Damage; Humanities and Social Sciences; Life Sciences; Mice, Knockout; multidisciplinary; Neoplasm Metastasis; Neurogenesis; Nuclear Envelope - metabolism; Science; Science (multidisciplinary); Stress, Mechanical
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18580-9

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.