AffiliationDivision of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, 555 Wilmslow Road, Manchester M20 4GJ, UK
MetadataShow full item record
AbstractThe 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.
CitationLittler S, Sloss O, Geary B, Pierce A, Whetton AD, Taylor SS. Oncogenic MYC amplifies mitotic perturbations. Open Biol. 2019 Aug 30;9(8):190136.
- c-MYC delays prometaphase by direct transactivation of MAD2 and BubR1: identification of mechanisms underlying c-MYC-induced DNA damage and chromosomal instability.
- Authors: Menssen A, Epanchintsev A, Lodygin D, Rezaei N, Jung P, Verdoodt B, Diebold J, Hermeking H
- Issue date: 2007 Feb 1
- Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYC-dependent sensitivity to anti-mitotic agents.
- Authors: Perera D, Venkitaraman AR
- Issue date: 2016 Jul 14
- c-Myc overexpression uncouples DNA replication from mitosis.
- Authors: Li Q, Dang CV
- Issue date: 1999 Aug
- Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co-repressor Ski.
- Authors: Marcelain K, Armisen R, Aguirre A, Ueki N, Toro J, Colmenares C, Hayman MJ
- Issue date: 2012 Jan
- Deregulation of the centrosome cycle and the origin of chromosomal instability in cancer.
- Authors: Lingle WL, Lukasiewicz K, Salisbury JL
- Issue date: 2005