Aneuploidy: implications for protein homeostasis and disease

Abstract

It has long been appreciated that aneuploidy - in which cells possess a karyotype that is not a multiple of the haploid complement - has a substantial impact on human health, but its effects at the subcellular level have only recently become a focus of investigation. Here, we summarize new findings characterizing the impact of aneuploidy on protein quality control. Because aneuploidy has been associated with many diseases, foremost among them being cancer, and has also been linked to aging, we also offer our perspective on whether and how the effects of aneuploidy on protein quality control could contribute to these conditions. We argue that acquiring a deeper understanding of the relationship between aneuploidy, disease and aging could lead to the development of new anti-cancer and anti-aging treatments.

Keywords: Aneuploidy; Disease; Protein folding.

Fig. 1.

Aneuploidy causes proteotoxic stress. (A) Cells use protein quality-control (QC) and feedback mechanisms to maintain subunit stoichiometries of complexes whose subunits are encoded by different chromosomes. The protein quality-control machinery ensures accurate folding and maintains complex subunits that lack a binding partner in a soluble state. Eventually, excess and misfolded subunits must be degraded, as illustrated here by the yellow subunit that has been produced in relative excess. (B) Changes in chromosome number in aneuploid cells (shown here as disomy of the green chromosome) lead to a genomic imbalance that results in stoichiometric protein imbalances. Every subunit encoded by an unbalanced chromosome that functions in a protein complex lacks its binding partner(s) and must rely on cellular chaperones to maintain solubility and, if no binding partner is found, on the cellular proteases for its eventual degradation. This can lead to an increased burden on the protein quality-control systems and the exhaustion of the cellular protein quality-control machinery.

Fig. 2.

Protein aggregates marked by Hsp104. Example of Hsp104 foci that form in budding yeast cells, imaged by differential interference contrast (DIC) and fluorescence microscopy, upon increasing protein misfolding. Wild-type budding yeast cells carrying the disaggregating protein chaperone Hsp104 fused to eGFP were imaged while growing at 25°C in rich medium (YPD) and after a 30-minute heat shock, which induces protein misfolding, at 37°C. Hsp104-eGFP is diffusely localized throughout the cell under normal growth conditions, but heat-shocked cells accumulate protein aggregates that are seen as Hsp104–eGFP foci.