Coordination of Nuclear Envelope Assembly and Chromosome Segregation in Metazoan Cells
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CitationLiu, Shiwei. 2019. Coordination of Nuclear Envelope Assembly and Chromosome Segregation in Metazoan Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractDefects in the architecture or integrity of the nuclear envelope (NE) are associated with a variety of human diseases. Micronuclei, one common nuclear aberration, are an origin for chromothripsis, a catastrophic mutational process that is commonly observed in cancer. Micronuclei can originate from mis-segregated chromosomes that recruit their own NE originated from the endoplasmic reticulum (ER) network during mitotic exit. Micronuclei typically exhibit defective DNA replication and are prone to undergo abrupt loss of NE integrity, which generates DNA fragmentation and gives rise to chromothripsis. Despite its importance, the basis for of the NE defects of micronuclei is not known.
Here we show that micronuclei undergo defective NE assembly. Only “core” NE proteins assemble efficiently on lagging chromosomes, whereas “non-core” NE proteins, including nuclear pore complexes (NPCs), do not. Consequently, micronuclei fail to properly import key proteins that are necessary for the integrity of the NE and genome. We show that spindle microtubules inhibit assembly of non-core NE proteins on lagging chromosomes, causing an irreversible defect in NE assembly. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective NE assembly, prevent spontaneous NE disruption, and suppress DNA damage in micronuclei.
These findings and new preliminary data suggest that the following model for the assembly of the isolated core membrane domain on micronuclei. We propose that during NE assembly, large ER sheets containing NPC precursors are excluded from the spindle whereas ER “tubules” can efficiently infiltrate the spindle and assemble a core domain on lagging chromosomes. Our preliminary data suggests that the formation of ER tubules in mitosis requires F-actin and disruption of actin assembly coverts mitotic ER tubules into ER sheets. Thus, the organization of the mitotic spindle and the mitotic actin network spatially patterns NE assembly, largely through effects on the morphology of the ER network. We suggest that NE assembly is therefore error prone with only loose coordination of chromosome segregation and NE assembly. The absence of precise checkpoint controls may explain why errors during mitotic exit are frequent and often trigger catastrophic genome rearrangements.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42013068
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