Consequences of Micronucleation and Rupture
As it arises from chromosome missegregation, micronucleation is often accompanied by aneuploidy. In addition, reduced functionality in micronuclei leads to defects in transcription and DNA replication that render the cell functionally aneuploid even when chromosomes are segregated correctly. Aneuploidy causes a broad stress response in cells and its coincidence with micronucleation led us to investigate whether aneuploidy responses were reflective of micronucleation or micronucleus rupture. Addressing this question would also provide broad information about the cellular consequences of micronucleation and rupture for the cell in the initial and subsequent cell cycles.
To achieve this goal, we collaborated with Dr. Doug Fowler’s lab at the University of Washington to apply their Visual Cell Sorting technology to micronucleated cells (Hasle et al., Mol Systems Biol, 2020; DiPeso et al., bioRxiv, 2023). Combining their technology with a neural net trained to segment micronuclei in low resolution images of live cells allowed us to isolate cells from aneuploid populations with intact and ruptured micronuclei by flow cytometry. Our initial results comparing the effects of chromosome missegregation versus micronucleation and micronucleus rupture suggest that micronucleus rupture has a limited but important contribution to upregulating stress response genes in aneuploid cells and current work is focused on extending these assays to different cellular conditions.
Projects
- How does the chromatin content of the micronucleus affect the cellular response?
- How does the presence of common cancer-associated genetic lesions alter the cellular response?
- Do micronucleated cells have a different potential than aneuploid cells for tumor formation?
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