Journal
CELL
Volume 158, Issue 3, Pages 633-646Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.05.046
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Funding
- European Molecular Biology Organization fellowship
- Marie Curie Intra-European fellowship [274093]
- Fondazione Umberto Veronesi postdoctoral fellowship
- Associazione Italiana per la Ricerca sul Cancro
- Association for International Cancer Research
- Telethon-Italy
- CEN-Italy
- Ministero dell'Istruzione Universitaria e della Ricerca
- Danish Cancer Society
- Lundbeck Foundation
- Danish Council for Independent Research
- European Commission
- Mechanobiology Institute, NUS, Singapore
- Novo Nordisk Fonden [NNF12OC0002290] Funding Source: researchfish
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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.
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