Nuclear Damage in Highly Constrained Migration: From Lamina Defects to DNA Breaks

Abstract

Cells in vivo are sometimes required to migrate through tight spaces that are much smaller than the largest organelle, their nucleus. Micro-pore migration of lung cancer cells causes nuclear blebs with segregated lamins as well as DNA tethering and breaks. Nuclear blebs seen in the majority of cells are enriched in lamin-A and deficient in both lamin-B and DNA, but the cells are viable with a normal rate of post-migration proliferation. Phosphorylation of lamin-A, which relates to turnover under low stress, decreases with migration, while phosphomimetic and progeria mutants of lamin-A exhibit distinct differences. Knockdown of lamin-A induced the frequent formation of DNA tethers that extrude from the main nuclear body through a gap in lamin-B and to the pore that the cell migrated through. Double strand breaks also increased and are consistent with subsequent cell death. The findings reveal a crucial role for the lamins in cell migration and survival, likely through DNA protection.