HSF 1 deficiency and impaired HSP 90‐dependent protein folding are hallmarks of aneuploid human cells

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 PIDDosome activates p53 in response to supernumerary centrosomes

“…All of these features are well-known consequences of increased centrosomes, DNA ploidy, or aneuploidy (Davoli and de Lange 2011;Puccini et al 2013;Donnelly et al 2014). Furthermore, our data reveal a genuine physiological role of the PIDDosome in centrosome counting and uncover the missing link between supernumerary centrosomes and p53.…”

The deregulated microRNAome contributes to the cellular response to aneuploidy

“…To determine the effects of chromosome gain on miRNA expression in human cells, we used a series of cells derived from HCT116 and RPE1 cell lines that contain one or more extra copies of different chromosomes ( [5,9,12], Fig. 1a, see Methods for more details).…”

“…Recently developed aneuploid model systems in several different species have accelerated research on the effects of aneuploidy per se. The physiological changes in response to an unbalanced karyotype are multifold, including impaired proliferation, replication stress and proteotoxic stress that is characterized by changes in protein stoichiometry, reduced protein folding capacity and by activation of autophagy [4][5][6][7][8][9][10][11][12][13]. The physiological response to aneuploidy goes hand in hand with a transcriptional response that is manifested in a conserved pathway deregulation [14,15].…”

Too much to handle — how gaining chromosomes destabilizes the genome

“…The reduced levels of replicative factors might be explained by the defective folding capacity that has been observed in aneuploid cells. 36,37 Several proteins involved in DNA repair and replication are well-characterized clients of molecular chaperones. 38 Specifically Hsp90 contributes to genomic integrity, as it is an essential factor for telomerase activity.…”

“…41 Strikingly, the proteome changes in HeLa cells upon Hsp90 inhibition show a marked similarity to those observed in untreated aneuploid cell lines; 42 the common downregulated pathways include DNA and RNA metabolism as well as cell cycle pathways. 37 The insufficient Hsp90 capacity of aneuploids will lead to the incorrect folding of client proteins; these unfolded, non-functional proteins then aggregate in cytoplasmic deposits or are degraded. Although there has been no evidence available so far that MCM2-7 proteins are direct clients of Hsp90-mediated protein folding, the fact that protein levels of MCM2-7 are more heavily reduced than the mRNA levels in aneuploid cells should prompt investigation into the Figure 2.…”