Causes and consequences of protein folding stress in aneuploid cells

Imbalanced chromosomal content, or aneuploidy, strongly affects the physiology of eukaryotic cells. The consequences of these effects are frequently detrimental, in particular in Metazoans. In humans, aneuploidy has been causatively linked to pathological conditions such as spontaneous abortions, trisomy syndromes and cancer. However, only in recent years have we witnessed an unraveling of the complex phenotypes that are caused by aneuploidy. Importantly, it has become apparent that aneuploidy evokes global and uniform changes that cannot be explained by the altered expression of the specific genes located on aneuploid chromosomes. Recent discoveries show that aneuploidy negatively affects protein folding; in particular, the functions of the molecular chaperone Heat Shock Protein 90 (HSP90) and the upstream regulator of heat shock-induced transcription, Heat Shock Factor 1 (HSF1), are impaired. Here we discuss the possible causes and consequences of this impairment and propose that the protein folding stress instigated by aneuploidy may be a common feature of conditions as variable as cancer and trisomy syndromes.