Chromosome length and gene density contribute to micronuclear membrane stability

Abstract

Micronuclei are derived from missegregated chromosomes and frequently lose membrane integrity, leading to DNA damage, innate immune activation, and metastatic signaling. Here we demonstrate that two characteristics of the trapped chromosome, length and gene density, are key contributors to micronuclei membrane stability in human cells. Chromosome length is proportional to micronuclei size, and gene density has an additive effect with micronucleus size on membrane stability. We demonstrate that these results are not due to chromosome-specific differences in spindle position or initial nuclear pore complex recruitment during post-mitotic nuclear envelope assembly. We find that chromosome length and micronuclei size strongly correlate with lamin B1 and nuclear pore density in intact micronuclei. Unexpectedly, lamin B1 levels do not predict nuclear lamina organization and membrane stability. Instead, small gene-dense micronuclei have decreased nuclear lamina gaps compared to large micronuclei, despite very low levels of lamin B1. Our data strongly suggest that nuclear envelope composition defects previously correlated with membrane rupture only partly explain membrane stability in micronuclei. We propose that an unknown factor linked to gene density has a separate function that inhibits the appearance of nuclear lamina gaps and delays membrane rupture until late in the cell cycle.