Catastrophic Nuclear Envelope Collapse in Cancer Cell Micronuclei

• Published in: Cell Vol. 154; no. 1; pp. 47 - 60
• Main Authors: Hatch, Emily M., Fischer, Andrew H., Deerinck, Thomas J., Hetzer, Martin W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.07.2013
• Subjects: aneuploidy; biomarkers; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Nucleus - metabolism; chromatin; DNA Damage; endoplasmic reticulum; Genomic Instability; Humans; Interphase; Lamins - metabolism; lung neoplasms; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Micronuclei, Chromosome-Defective; Nuclear Envelope - metabolism; nuclear membrane
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.06.007

During mitotic exit, missegregated chromosomes can recruit their own nuclear envelope (NE) to form micronuclei (MN). MN have reduced functioning compared to primary nuclei in the same cell, although the two compartments appear to be structurally comparable. Here we show that over 60% of MN undergo an irreversible loss of compartmentalization during interphase due to NE collapse. This disruption of the MN, which is induced by defects in nuclear lamina assembly, drastically reduces nuclear functions and can trigger massive DNA damage. MN disruption is associated with chromatin compaction and invasion of endoplasmic reticulum (ER) tubules into the chromatin. We identified disrupted MN in both major subtypes of human non-small-cell lung cancer, suggesting that disrupted MN could be a useful objective biomarker for genomic instability in solid tumors. Our study shows that NE collapse is a key event underlying MN dysfunction and establishes a link between aberrant NE organization and aneuploidy. [Display omitted] [Display omitted] •Micronuclei frequently undergo irreversible nuclear-envelope collapse•Lamin B1 levels influence the likelihood of nuclear-envelope collapse•Massive DNA-damage accumulation in micronuclei can occur upon collapse•Micronuclei disruption occurs in solid tumors as well as normal and cancer cells Missegregated chromosomes recruit their own nuclear envelope to form micronuclei (MN). Most MN are disrupted due to nuclear-envelope collapse, and this leads to impaired chromosome function. Disrupted MN may therefore serve as a biomarker for genomic instability in solid tumors.