ATR controls chromosome integrity and chromatin dynamics. We have previously shown that yeast Mec1/ATR promotes chromatin detachment from the nuclear envelope to counteract aberrant topological transitions during DNA replication. Here, we provide evidence that ATR activity at the nuclear envelope responds to mechanical stress. Human ATR associates with the nuclear envelope during S phase and prophase, and both osmotic stress and mechanical stretching relocalize ATR to nuclear membranes throughout the cell cycle. The ATR-mediated mechanical response occurs within the range of physiological forces, is reversible, and is independent of DNA damage signaling. ATR-defective cells exhibit aberrant chromatin condensation and nuclear envelope breakdown. We propose that mechanical forces derived from chromosome dynamics and torsional stress on nuclear membranes activate ATR to modulate nuclear envelope plasticity and chromatin association to the nuclear envelope, thus enabling cells to cope with the mechanical strain imposed by these molecular processes.

Danish Cancer Society Research Center 2100 Copenhagen Denmark; Institute of Molecular Genetics v v i Academy of Sciences of the Czech Republic 14220 Prague Czech Republic

Fondazione Istituto FIRC di Oncologia Molecolare Via Adamello 16 20139 Milan Italy

Fondazione Istituto FIRC di Oncologia Molecolare Via Adamello 16 20139 Milan Italy; Università degli Studi di Milano 20122 Milan Italy

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University 77115 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University 77115 Olomouc Czech Republic; Danish Cancer Society Research Center 2100 Copenhagen Denmark; Institute of Molecular Genetics v v i Academy of Sciences of the Czech Republic 14220 Prague Czech Republic

Mechanobiology Institute and Department of Biological Sciences National University of Singapore 117411 Singapore Singapore

Università degli Studi di Milano 20122 Milan Italy

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Nat Rev Mol Cell Biol. 2014 Sep;15(9):559. doi: 10.1038/nrm3864. PubMed

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