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No Chromosome Left Behind: Mechanisms That Allow Lagging Chromosomes to Enter Daughter Nuclei

  • Author(s): Warecki, Brandt
  • Advisor(s): Sullivan, William
  • et al.
Abstract

Cells that divide with lagging chromosomes risk losing key genetic information if those chromosomes are not incorporated into daughter nuclei. When the nuclear envelope reforms a physical barrier around the daughter nucleus, lagging chromosomes are expected to be locked out of the nucleus and form damage-prone micronuclei. While micronuclei occur fairly frequently in cancer cells, lagging chromosomes can still sometimes enter telophase daughter nuclei to preserve euploidy. However, very little is known about the cellular mechanisms that allow lagging chromosomes to reintegrate into daughter nuclei and maintain genome integrity. In Drosophila, lagging chromosome fragments lacking a centromere, called acentrics, are capable of efficient reintegration into telophase daughter nuclei. Acentrics remain connected to daughter nuclei through a DNA tether. The tether is coated with Polo kinase, BubR1 kinase, Aurora B kinase, and INCENP, but the function of the tether is poorly understood. Here, I use Drosophila as a model system to identify mechanisms that promote lagging chromosome reintegration. I find that dividing with lagging chromosomes triggers the formation of highly localized gaps in the nascent nuclear envelope surrounding daughter nuclei. These gaps form channels through which acentrics pass to enter into daughter nuclei. Channel formation requires the pool of Aurora B kinase localized to the tether. Aurora B kinase phosphorylates chromatin on the acentric and at the site of acentric entry, keeping this chromatin in a mitotic state that prevents the recruitment of nuclear envelope components, leading to gap formation. Furthermore, I find that while acentrics are free of lamin and nuclear pore complexes, nuclear membrane frequently contacts acentrics during reintegration. Fusion between membrane on the acentric and membrane on the nucleus guides the acentric through the channel. The membrane fusion protein Comt/NSF and the ESCRT-III component Shurb/CHMP4B are required for these fusion events and efficient acentric entry into daughter nuclei. Taken together, these results uncover novel mechanisms by which lagging chromosomes can rejoin daughter nuclei to preserve the integrity of the genome.

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