Aneuploidy and Protein Homeostatic Imbalance

Abstract

Aneuploidy is an aberrant condition that a cell harbours incorrect chromosome numbers or identities often resulted from mitotic errors. Aneuploidy impacts cellular functions, developmental programme and affects individual fitness, and leads to examples such as Down syndrome and tumours. The gain or loss of large amount of genes caused by chromosome copy‐number changes can alter metabolic programmes and protein homeostasis. In most circumstances, the elicited stress responses which are detrimental to cellular and organismal fitness. However, in cancer cells, same stresses may be beneficial to pose adaptive potentials. In this article, the paradox of aneuploidy is discussed, and the triggering of aneuploidy‐associated protein homeostatic imbalance which may serve as a strategy to treat cancer.

Key Concepts

  • Aneuploidy is a situation that a cell harbours aberrant number of chromosomes that is not a multiple of the haploid complement.
  • Aneuploidy is mostly caused by mitotic errors and is irreversible in cells.
  • Aneuploidy generally resulted in adverse effect in both cellular and organismal levels; however, in stress conditions it may facilitate adaptation.
  • Aneuploidy causes protein homeostatic imbalance; thus, the proteotoxic property in cancer cells may apply as treatment for tumours.

Keywords: aneuploidy; chaperone; chromosome instability; protein homeostatic imbalance; protein quality control

Figure 1. The spindle assembly checkpoint system. Spindle assembly checkpoint (SAC) is employed during cell cycles to ensure that the sister chromatids are correctly aligned before cell division. Several proteins, including BUB1, BUB3 and MAD2 are involved in SAC, and mainly act as inhibitors for APC/C. Once microtubule‐kinetochore attachments are properly built, CDC20/APC/C initiates the degradation of securin, and releases active separase to hydrolyse cohesin, further separates sister chromatids.
Figure 2. The protein quality control system. The protein homeostasis maintenance is executed by protein quality control system, which includes protein synthesis, folding, trafficking and degradation processes. Chaperones mediate the co‐translational folding of nascent polypeptides and post‐translational refolding at some circumstances. For unfolded, misfolded, or aggregation proteins that are targeted for degradation, chaperones can as well assist their presentation to the ubiquitin‐proteasome system (UPS) and autophagy system for irreversibly proteolytic degradation.
Figure 3. The proteotoxic stress caused by aneuploidy. In euploid cells, protein quality control system is active to maintain correct stoichiometry for functional complexes composed by subunit A and B. Subunit A and B are encoded by chromosome 1 and 2, respectively. In aneuploidy situation with additional chromosome 2, extra subunit B fails to complex with subunit A for functional dimer, thus is structurally unstable in the bulk and waits for degradation. A vast gain or loss of gene products will challenge and deplete chaperones, the UPS and autophagy system from the physiological tasks, therefore eventually cause protein homeostatic imbalance.
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Tang, Yun‐Chi(Jul 2015) Aneuploidy and Protein Homeostatic Imbalance. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025987]