Cellular Stress Associated with Aneuploidy

Abstract

Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells.

Keywords: aneuploidy; metabolic stress; mitotic stress; proteotoxic stress; replication stress.

Figure 1.

Effects of aneuploidy on the transcriptome and proteome due to the alteration of gene dosage. Changes to relative chromosome dosage (A) in aneuploidy (shown here as a euploid cell becoming trisomic for the blue chromosome) results in scaled changes to the RNA (B) and protein (C) expression level of genes carried on the aneuploid chromosome as is the case for direct effects of aneuploidy (D). However, indirect effects or trans-activating effects (E) of aneuploidy can alter the expression of genes on other chromosomes by increasing transcription factor levels to promote expression or by having an epigenetic effect such as de-silencing genes. Globular circles denote gene products that scale accordingly with chromosome number.

Figure 2.

The major categories of aneuploidy-associated stresses discussed in this review. As shown by the black arrows pointing to the four stresses. Aneuploidy leads to mitotic stress such as lagging chromosomes, replication stress via stalled and delayed replication fork progression, metabolic stress usually related to increased ROS levels in the mitochondria, and proteotoxic stress that overwhelms the proteasome. In addition to aneuploidy causing stress, some of the stresses can further perpetuate aneuploidization through causing different stress and increasing CIN (black arrows pointing between stressed and back toward aneuploidization). For example, aneuploid cells may produce more ROS that can damage DNA leading to replication stress and mitotic error.