Consequences of a tight squeeze: Nuclear envelope rupture and repair

Abstract

ABSTRACTCell migration through tight spaces can induce substantial deformations of the nucleus and cause nuclear envelope (NE) rupture, resulting in uncontrolled exchange of nuclear and cytosolic proteins. These events can cause DNA damage and, in severe cases, nuclear fragmentation, challenging the integrity of the genomic material. Cells overcome NE ruptures during interphase by repairing the NE using components of the endosomal sorting complexes required for transport (ESCRT) machinery. Paralleling the molecular mechanism used during NE reformation in late mitosis, ESCRT-III subunits and the associated AAA-ATPase VPS4B are recruited to NE rupture sites and help restore NE integrity. While these findings are common to many cell types, they are particularly relevant in the context of cancer metastasis, where nuclear deformation and rupture could drive genomic instability in invading cells and further promote cancer progression. At the same time, inhibiting NE repair may offer new therapeutic approaches to specifically target invasive cancer cells.