Defective assembly of the nuclear envelope and nuclear pore complex in micronuclei may underlie chromothripsis.
Major finding: Defective assembly of the nuclear envelope and nuclear pore complex in micronuclei may underlie chromothripsis.
Mechanism: Spindle microtubules disrupted assembly of non-core nuclear envelope proteins on lagging chromosomes.
Impact: The lack of a chromosome separation checkpoint may explain the high frequency of chromothripsis in cancer.
Chromothripsis is a catastrophic mutational process resulting in chromosome fragmentation that occurs frequently in cancer and can arise from micronuclei after they spontaneously lose their nuclear envelope integrity. However, the underlying cause of micronucleus nuclear envelope fragility remains unknown, prompting Liu, Kwon, and colleagues to investigate the assembly of nuclear envelopes on lagging chromosomes in micronuclei compared with primary nuclei. During normal nuclear envelope assembly two groups of proteins transiently assemble on different parts of the chromosomes: “core” proteins concentrate near the spindle and “non-core” proteins concentrate away from the spindle. The core nuclear envelope proteins were recruited to lagging chromosomes at equivalent or higher levels compared with the main chromosome mass, whereas nuclear pore complex proteins and other non-core proteins failed to assemble almost completely. This defect in nuclear envelope and nuclear pore complex assembly in micronuclei resulted in defective import and accumulation of nuclear proteins. Spindle microtubules irreversibly blocked assembly of nuclear pore complexes and other non-core nuclear envelope proteins on lagging chromosomes independent of aurora B, and positioning missegregated chromosomes away from the spindle corrected the defective nuclear envelope assembly and suppressed DNA damage in micronuclei. These findings were inconsistent with a previously proposed “chromosome separation checkpoint.” Instead, these finding suggest that chromosome segregation and nuclear envelope assembly are loosely coordinated by the timing of mitotic spindle disassembly. The lack of a precise checkpoint may underlie errors during mitotic exit and the irreversibility of nuclear assembly defects during mitotic exit may explain the frequency of chromothripsis in cancer.
Liu S, Kwon M, Mannino M, Yang N, Renda F, Khodjakov A, et al. Nuclear envelope assembly defects link mitotic errors to chromothripsis. Nature 2018;561:551–5.
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