The pleiotropic deubiquitinase Ubp3 confers aneuploidy tolerance.
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.
Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Stacie E
SE
Dodgson
Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Stefano
S
Santaguida
Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Sharon
S
Kim
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Jason
J
Sheltzer
Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Angelika
A
Amon
D000782:Aneuploidy; D000818:Animals; D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
D029701:Saccharomyces cerevisiae Proteins; C431363:USP10 protein, human; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; D046988:Proteasome Endopeptidase Complex; C101111:UBP3 protein, S cerevisiae
Ubp3; aneuploidy; deubiquitinase; proteasome