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.
Highlights
MYC, a basic helix-loop-helix zipper transcription factor, regulates the expression of vast arrays of genes in context-specific manners via transcriptional amplification and cofactor-dependent regulation [1,2,3]
When MYC was expressed at higher levels (500 ng ml−1 tetracycline) apoptosis was induced, leading to an increased doubling time
We identified fourteen proteins involved in mitosis, including three kinesin-related motor proteins, KIF2C/MCAK, KIF11/Eg5 and KIF22KID, plus proteins involved in kinetochore function and the spindle assembly checkpoint (SAC), namely NDC80, CENPV, MAD2L1 and CDC20
Summary
MYC, a basic helix-loop-helix zipper (bHLHZ) transcription factor, regulates the expression of vast arrays of genes in context-specific manners via transcriptional amplification and cofactor-dependent regulation [1,2,3]. The synthetic lethality may arise not because overexpressing MYC affects mitosis directly, but rather because cells with elevated MYC are more efficiently eliminated via apoptosis following the abnormal mitoses induced by inhibiting mitotic regulators [27,28,29]. To explore these two possibilities, we set out to examine how modulating MYC expression influences the fidelity of chromosome segregation and cell fate in response to mitotic perturbations, and to try to resolve MYC functions in terms of mitotic regulation versus the apoptotic response to mitotic anomalies. We created a model system that allows MYC function to be tightly controlled, we used timelapse microscopy and cell fate profiling to determine the effect MYC overexpression has on mitotic chromosome segregation, both in unperturbed cell cycles and in response to an array of anti-mitotic agents
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