The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance
Name
Genes Dev.-2016-Dodgson-2259-71.pdf
Size
1.03 MB
Format
Adobe PDF
Checksum (MD5)
906f824128724d4b20a9508eee62347c
Author(s)
Sheltzer, Jason
Dodgson, Stacie Elizabeth
Santaguida, Stefano
Kim, Sharon H.
Amon, Angelika B.
Date Issued
October 2016
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Citation
Dodgson, Stacie E., et al. “The Pleiotropic Deubiquitinase Ubp3 Confers Aneuploidy Tolerance.” Genes & Development, vol. 30, no. 20, Oct. 2016, pp. 2259–71.
Version
Final published version
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. Keywords: aneuploidy; Ubp3; deubiquitinase; proteasome]
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1101/GAD.287474.116
