Aneuploidy in Cancer and Aging

Abstract

Chromosomal instability (CIN), the persistent inability of a cell to faithfully segregate its genome, is a feature of many cancer cells. It stands to reason that CIN enables the acquisition of multiple cancer hallmarks; however, there is a growing body of evidence suggesting that CIN impairs cellular fitness and prevents neoplastic transformation. Here, we suggest a new perspective to reconcile this apparent paradox and share an unexpected link between aneuploidy and aging that was discovered through attempts to investigate the CIN-cancer relationship. Additionally, we provide a comprehensive overview of the function and regulation of the anaphase-promoting complex, an E3 ubiquitin ligase that mediates high-fidelity chromosome segregation, and describe the mechanisms that lead to whole-chromosome gain or loss. With this review, we aim to expand our understanding of the role of CIN in cancer and aging with the long-term objective of harnessing this information for the advancement of patient care.

Keywords: anaphase-promoting complex/cyclosome; chromosomal instability.

Figure 1

Structure and function of the anaphase–promoting complex/cyclosome (APC/C). The APC/C is a multimeric, cullin-RING E3 ubiquitin (Ub) ligase. It is organized into three domains: the platform (blue), the tetratricopeptide repeat (TPR) lobe (yellow), and the catalytic core (green). The coactivating proteins Cdc20 and Cdh1 form a bipartite destruction-box (D–box) receptor (DBR; red) together with the Apc10 subunit. Cullin (Apc2) and RING (Apc11) simultaneously bind the E2 ubiquitin complex and the substrate (sub) to facilitate a nucleophilic substitution reaction between the amino group of a lysine (K) residue on the substrate and the thioester bond of the E2-Ub intermediate. Adapted with permission from Macmillan Publishers Ltd: Nat. Rev. Mol. Cell Biol. 16, 82–94 (2015), Reference 118.

Figure 2

Molecular mechanisms of anaphase-promoting complex/cyclosome (APC/C) inhibition. (a) The mitotic checkpoint complex (MCC), early mitotic inhibitor 1 (Emi1), and Mad2L2 sequester Cdc20 or Cdh1 and prevent the coactivation of the APC/C. (b) Pseudosubstrate inhibitors, including BubR1 and Emi1, bind the bipartite D-box receptor (shown in red) and prevent substrate (Sub) recruitment to the APC/C. (c) Emi1 inhibits ubiquitin (Ub) chain extension. The Nup98-Rae1 subcomplex is most likely to function as a ligase inhibitor; however, this hypothesis remains untested. The red triangle signifies the bipartite D-box receptor

Figure 3

Cellular mechanisms of whole-chromosome aneuploidy. During metaphase, when microtubules emanating from each spindle pole attach to their proximal sister kinetochore, the attachment is said to be amphitelic (green). The result of this type of attachment is proper segregation of the sister chromatids into each daughter cell. When microtubules from one spindle pole attach to both sister kinetochores, a syntelic attachment is formed (yellow). Syntelic attachments cause chromosome missegregation in the form of hidden chromatids. Merotelic attachments (red) are formed when one sister kinetochore is properly attached to microtubules originating from its proximal spindle pole while the other kinetochore is attached to microtubules from both spindle poles. Merotelic attachments lead to lagging chromatids.

Figure 4

The gain/loss theory. Following a gross chromosome missegregation event, two aneuploid daughter cells exist, one with a net chromosome loss (2N – 1) and the other with a net chromosome gain (2N + 1). One fate of the 2N – 1 cell is to undergo transformation because of the loss of tumor suppressors. The 2N + 1 cell is more apt to undergo apoptosis or senescence/cell cycle arrest owing to increased proteotoxicity, which together promote aging.