ATR Mediates a Checkpoint at the Nuclear Envelope in Response to Mechanical Stress

Summary

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.

Graphical Abstract

Highlights

• •

  ATR localizes at the nuclear envelope in S phase and prophase

• •

  ATR responds to mechanical stress by relocalizing to the nuclear envelope

• •

  The ATR mechanical response is fast and reversible

• •

  ATR coordinates chromatin condensation and nuclear envelope breakdown

Abstract

ATR responds to various kinds of mechanical stress by relocating to the nuclear envelope and signaling, independent of the DNA-damage response pathway. ATR may enable cells to cope with mechanical strain imposed by molecular processes, such as chromosome dynamics.