Dodgson, S. E., Santaguida, S., Kim, S., Sheltzer, J., Amon, A. (November 2016) The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance. Genes Dev. ISSN 1549-5477 (Electronic)0890-9369 (Linking)
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Abstract
Aneuploidy-or an unbalanced karyotype in which whole chromosomes are gained or lost-causes reduced fitness at both the cellular and organismal levels but is also a hallmark of human cancers. Aneuploidy causes a variety of cellular stresses, including genomic instability, proteotoxic and oxidative stresses, and impaired protein trafficking. The deubiquitinase Ubp3, which was identified by a genome-wide screen for gene deletions that impair the fitness of aneuploid yeast, is a key regulator of aneuploid cell homeostasis. We show that deletion of UBP3 exacerbates both karyotype-specific phenotypes and global stresses of aneuploid cells, including oxidative and proteotoxic stress. Indeed, Ubp3 is essential for proper proteasome function in euploid cells, and deletion of this deubiquitinase leads to further proteasome-mediated proteotoxicity in aneuploid yeast. Notably, the importance of UBP3 in aneuploid cells is conserved. Depletion of the human homolog of UBP3, USP10, is detrimental to the fitness of human cells upon chromosome missegregation, and this fitness defect is accompanied by autophagy inhibition. We thus used a genome-wide screen in yeast to identify a guardian of aneuploid cell fitness conserved across species. We propose that interfering with Ubp3/USP10 function could be a productive avenue in the development of novel cancer therapeutics.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Ubp3 aneuploidy deubiquitinase proteasome |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomal duplications > aneuploidy diseases & disorders > cancer > drugs and therapies bioinformatics > genomics and proteomics > genetics & nucleic acid processing > genomes organism description > yeast |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL labs > Sheltzer lab |
| Depositing User: | Matt Covey |
| Date: | 2 November 2016 |
| Date Deposited: | 15 Nov 2016 15:24 |
| Last Modified: | 08 Jul 2021 14:34 |
| PMCID: | PMC5110993 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33886 |
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