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

Gururaj Rao Kidiyoor, Qingsen Li, Giulia Bastianello, Christopher Bruhn, Irene Giovannetti, Adhil Mohamood, Galina V. Beznoussenko, Alexandre Mironov, Matthew Raab, Matthieu Piel, Umberto Restuccia, Vittoria Matafora, Angela Bachi, Sara Barozzi, Dario Parazzoli, Emanuela Frittoli, Andrea Palamidessi, Tito Panciera, Stefano Piccolo, Giorgio Scita, Paolo Maiuri, Kristina M. Havas, Zhong-Wei Zhou, Amit Kumar, Jiri Bartek, Zhao-Qi Wang and Marco Foiani ()
Additional contact information
Gururaj Rao Kidiyoor: IFOM- FIRC Institute of Molecular Oncology
Qingsen Li: IFOM- FIRC Institute of Molecular Oncology
Giulia Bastianello: IFOM- FIRC Institute of Molecular Oncology
Christopher Bruhn: IFOM- FIRC Institute of Molecular Oncology
Irene Giovannetti: IFOM- FIRC Institute of Molecular Oncology
Adhil Mohamood: IFOM- FIRC Institute of Molecular Oncology
Galina V. Beznoussenko: IFOM- FIRC Institute of Molecular Oncology
Alexandre Mironov: IFOM- FIRC Institute of Molecular Oncology
Matthew Raab: Institut Curie/CNRS
Matthieu Piel: Institut Curie/CNRS
Umberto Restuccia: IFOM- FIRC Institute of Molecular Oncology
Vittoria Matafora: IFOM- FIRC Institute of Molecular Oncology
Angela Bachi: IFOM- FIRC Institute of Molecular Oncology
Sara Barozzi: IFOM- FIRC Institute of Molecular Oncology
Dario Parazzoli: IFOM- FIRC Institute of Molecular Oncology
Emanuela Frittoli: IFOM- FIRC Institute of Molecular Oncology
Andrea Palamidessi: IFOM- FIRC Institute of Molecular Oncology
Tito Panciera: University of Padova
Stefano Piccolo: IFOM- FIRC Institute of Molecular Oncology
Giorgio Scita: IFOM- FIRC Institute of Molecular Oncology
Paolo Maiuri: IFOM- FIRC Institute of Molecular Oncology
Kristina M. Havas: IFOM- FIRC Institute of Molecular Oncology
Zhong-Wei Zhou: Leibniz Institute on Aging, Fritz Lipmann Institute
Amit Kumar: Genome and Cell Integrity Lab, CSIR-Indian Institute of Toxicology Research
Jiri Bartek: Danish Cancer Society Research Center
Zhao-Qi Wang: Leibniz Institute on Aging, Fritz Lipmann Institute
Marco Foiani: IFOM- FIRC Institute of Molecular Oncology

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18580-9

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