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Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
Published on: September 20, 2019
Oncogenic MYC amplifies mitotic perturbations
Samantha Littler1, Olivia Sloss1, Bethany Geary1,2
1Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK.
Abstract:
The oncogenic transcription factor MYC modulates vast arrays of genes, thereby influencing numerous biological pathways including biogenesis, metabolism, proliferation, apoptosis and pluripotency. When deregulated, MYC drives genomic instability via several mechanisms including aberrant proliferation, replication stress and ROS production. Deregulated MYC also promotes chromosome instability, but less is known about how MYC influences mitosis. Here, we show that deregulating MYC modulates multiple aspects of mitotic chromosome segregation. Cells overexpressing MYC have altered spindle morphology, take longer to align their chromosomes at metaphase and enter anaphase sooner. When challenged with a variety of anti-mitotic drugs, cells overexpressing MYC display more anomalies, the net effect of which is increased micronuclei, a hallmark of chromosome instability. Proteomic analysis showed that MYC modulates multiple networks predicted to influence mitosis, with the mitotic kinase PLK1 identified as a central hub. In turn, we show that MYC modulates several PLK1-dependent processes, namely mitotic entry, spindle assembly and SAC satisfaction. These observations thus underpin the pervasive nature of oncogenic MYC and provide a mechanistic rationale for MYC's ability to drive chromosome instability.
Insights
The oncogenic transcription factor MYC affects cell division, leading to chromosome instability. MYC
Area of Science:
- Cell Biology
- Molecular Oncology
- Genetics
Background:
- The transcription factor MYC is a key regulator of cellular processes.
- MYC deregulation contributes to genomic instability and cancer.
- The precise mechanisms by which MYC influences mitosis remain unclear.
Purpose of the Study:
- To investigate how deregulated MYC impacts mitotic chromosome segregation.
- To elucidate the role of MYC in driving chromosome instability during mitosis.
Main Methods:
- Overexpression of MYC in cells.
- Analysis of mitotic spindle morphology and chromosome alignment.
- Assessment of mitotic anomalies and micronuclei formation.
- Proteomic analysis to identify MYC-interacting partners and pathways.
- Investigation of MYC's effect on Polo-like kinase 1 (PLK1) activity.
Main Results:
- MYC overexpression alters spindle morphology and chromosome dynamics during mitosis.
- Cells with MYC overexpression exhibit increased sensitivity to anti-mitotic drugs, leading to more micronuclei.
- Proteomic analysis identified PLK1 as a central hub modulated by MYC.
- MYC influences PLK1-dependent processes including mitotic entry, spindle assembly, and spindle assembly checkpoint (SAC) satisfaction.
Conclusions:
- Deregulated MYC significantly impacts multiple aspects of mitosis and chromosome segregation.
- MYC's modulation of PLK1-dependent pathways provides a mechanistic link to MYC-driven chromosome instability.
- These findings highlight MYC's pervasive role in promoting genomic instability in cancer.
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