title: ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress.
abstract: 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.
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Mazzanti
authors.affiliation: Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77115 Olomouc, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Mistrik
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Kosar
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Galina V
authors.initials: GV
authors.lastname: Beznoussenko
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Mironov
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Garrè
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Parazzoli
authors.affiliation: Mechanobiology Institute and Department of Biological Sciences, National University of Singapore, 117411 Singapore, Singapore.
authors.forename: G V
authors.initials: GV
authors.lastname: Shivashankar
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy; Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Scita
authors.affiliation: 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. Electronic address: jb@cancer.dk.
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Via Adamello 16, 20139 Milan, Italy; Università degli Studi di Milano, 20122 Milan, Italy. Electronic address: marco.foiani@ifom.eu.
authors.forename: Marco
authors.initials: M
authors.lastname: Foiani
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D002843:Chromatin / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009685:Nuclear Envelope / Q000378:metabolism*; D009995:Osmosis; D011494:Protein Kinases / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D002843:Chromatin; D011494:Protein Kinases; C576897:Atr protein, mouse; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1
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