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Article

Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover

1
Department of Biochemistry & Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
2
Research Institute in Oncology & Hematology, CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(3), 531; https://doi.org/10.3390/cancers12030531
Received: 27 January 2020 / Revised: 21 February 2020 / Accepted: 24 February 2020 / Published: 25 February 2020
Chromosome instability (CIN), or progressive changes in chromosome numbers, is an enabling feature of many cancers; however, the mechanisms giving rise to CIN remain poorly understood. To expand our mechanistic understanding of the molecular determinants of CIN in humans, we employed a cross-species approach to identify 164 human candidates to screen. Using quantitative imaging microscopy (QuantIM), we show that silencing 148 genes resulted in significant changes in CIN-associated phenotypes in two distinct cellular contexts. Ten genes were prioritized for validation based on cancer patient datasets revealing frequent gene copy number losses and associations with worse patient outcomes. QuantIM determined silencing of each gene-induced CIN, identifying novel roles for each as chromosome stability genes. SKP1 was selected for in-depth analyses as it forms part of SCF (SKP1, CUL1, FBox) complex, an E3 ubiquitin ligase that targets proteins for proteolytic degradation. Remarkably, SKP1 silencing induced increases in replication stress, DNA double strand breaks and chromothriptic events that were ascribed to aberrant increases in Cyclin E1 levels arising from reduced SKP1 expression. Collectively, these data reveal a high degree of evolutionary conservation between human and budding yeast CIN genes and further identify aberrant mechanisms associated with increases in chromothriptic events. View Full-Text
Keywords: cancer; genome instability; chromosome instability; SCF complex; SKP1; cyclin E1; chromothripsis; single-cell quantitative imaging microscopy cancer; genome instability; chromosome instability; SCF complex; SKP1; cyclin E1; chromothripsis; single-cell quantitative imaging microscopy
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MDPI and ACS Style

Thompson, L.L.; Baergen, A.K.; Lichtensztejn, Z.; McManus, K.J. Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover. Cancers 2020, 12, 531. https://doi.org/10.3390/cancers12030531

AMA Style

Thompson LL, Baergen AK, Lichtensztejn Z, McManus KJ. Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover. Cancers. 2020; 12(3):531. https://doi.org/10.3390/cancers12030531

Chicago/Turabian Style

Thompson, Laura L.; Baergen, Allison K.; Lichtensztejn, Zelda; McManus, Kirk J. 2020. "Reduced SKP1 Expression Induces Chromosome Instability through Aberrant Cyclin E1 Protein Turnover" Cancers 12, no. 3: 531. https://doi.org/10.3390/cancers12030531

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