Gains or losses of entire chromosomes lead to aneuploidy, a condition tolerated poorly in all eukaryotes analyzed to date. How aneuploidy affects organismal and cellular physiology is poorly understood. We found that aneuploid budding yeast cells are under proteotoxic stress. Aneuploid strains are prone to aggregation of endogenous proteins as well as of ectopically expressed hard-to-fold proteins such as those containing polyglutamine (polyQ) stretches. Protein aggregate formation in aneuploid yeast strains is likely due to limiting protein quality-control systems, since the proteasome and at least one chaperone family, Hsp90, are compromised in many aneuploid strains. The link between aneuploidy and the formation and persistence of protein aggregates could have important implications for diseases such as cancer and neurodegeneration.
"Thus, proteome composition and the relative stoichiometries of proteins change dramatically during aging, presumably impeding overall proteostasis. A similar mechanism of proteostasis impairment has been suggested to occur as a result of aneuploidy (Oromendia et al., 2012; Stingele et al., 2012). Changes in transcript levels previously observed during aging (Budovskaya et al., 2008; Golden and Melov, 2004) contribute to the changes in protein abundance observed here, but the overall correlation is only moderate (R = 0.3) (Figure S1C). "
[Show abstract][Hide abstract] ABSTRACT: Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.
"Finally, aneuploid cells exhibit phenotypes characteristic of the disruption of protein homeostasis. Aneuploid yeast and mammalian cells harbor higher levels of protein aggregates and exhibit sensitivity to compounds that interfere with protein folding and turnover (Torres et al., 2007, 2010; Tang et al., 2011; Oromendia et al., 2012; Stingele et al., 2012; Donnelly et al., 2014). Here we investigate the molecular basis of one consequence of aneuploidy—genome instability. "
"Previously, it was shown that a loss-of-function mutation in the gene encoding the deubiquitinating enzyme Ubp6 also markedly alleviated the negative effects of aneuploidy including impaired proliferation and accumulation of cytoplasmic protein deposits in budding yeast (Torres et al, 2010; Oromendia et al, 2012). Here, we have identified the first aneuploidy-tolerating genetic modification in human cells. "
[Show abstract][Hide abstract] ABSTRACT: Aneuploidy is a hallmark of cancer and is associated with malignancy and poor prognosis. Recent studies have revealed that aneuploidy inhibits proliferation, causes distinct alterations in the transcriptome and proteome and disturbs cellular proteostasis. However, the molecular mechanisms underlying the changes in gene expression and the impairment of proteostasis are not understood. Here, we report that human aneuploid cells are impaired in HSP90-mediated protein folding. We show that aneuploidy impairs induction of the heat shock response suggesting that the activity of the transcription factor heat shock factor 1 (HSF1) is compromised. Indeed, increased levels of HSF1 counteract the effects of aneuploidy on HSP90 expression and protein folding, identifying HSF1 overexpression as the first aneuploidy-tolerating mutation in human cells. Thus, impaired HSF1 activity emerges as a critical factor underlying the phenotypes linked to aneuploidy. Finally, we demonstrate that deficient protein folding capacity directly shapes gene expression in aneuploid cells. Our study provides mechanistic insight into the causes of the disturbed proteostasis in aneuploids and deepens our understanding of the role of HSF1 in cytoprotection and carcinogenesis.
The EMBO Journal 09/2014; 33(20). DOI:10.15252/embj.201488648 · 10.43 Impact Factor
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