Figure 1. Sequence of events during NE rupture and repair.

Example of a cell experiencing NE rupture and repair during confined migration. Left, time-lapse sequence of cell migrating through collagen matrix, exhibiting nuclear bleb formation (white arrowhead), chromatin protrusion (red arrowhead) through a defect in the nuclear lamina (blue arrowhead), and NE rupture (red arrow). Images reproduced from [7]. Right, schematic representation of events. Cytoskeletal forces mediated by contractile/branching actin filaments (green) compress the nucleus and mediate its transit through the constriction. Red dashed boxes indicate regions depicted in image sequence. (i) Nucleus before it enters the constriction. (ii) Compression of the nucleus by the cytoskeleton and external confinement increases intranuclear pressure, resulting in detachment of the nuclear membranes from the underlying nuclear lamina and nuclear bleb formation at sites of local defects in the lamina (orange lining) and high nuclear curvature. (iii) Continuous nuclear compression results in expansion of the nuclear membrane bleb. Chromatin can protrude through the lamina defect into the bleb. (iv) Rupture of the nuclear membrane in the bleb allows uncontrolled exchange between the nuclear and cytoplasmic compartments. Nuclear deformation and NE rupture result in DNA damage (red stars). (v) Nuclear membrane repair by the ESCRT-III machinery (brown rectangle). (vi) DNA damage persists even after the nucleus has passed through the constriction and NE integrity has been restored. Please note that while the figure depicts NE rupture during confined migration, similar events occur during external compression of cells, and by compression of the nucleus through perinuclear actomyosin networks in adherent, but otherwise unconfined cells in 2D culture.