Aneuploidy and chromosomal instability: a vicious cycle driving cellular evolution and cancer genome chaos

Abstract

Aneuploidy and chromosomal instability frequently co-exist, and aneuploidy is recognized as a direct outcome of chromosomal instability. However, chromosomal instability is widely viewed as a consequence of mutations in genes involved in DNA replication, chromosome segregation and cell cycle checkpoints. Telomere attrition and presence of extra centrosomes have also been recognized as causative for errors in genomic transmission. Here, we examine recent studies suggesting that aneuploidy itself can be responsible for the procreation of chromosomal instability. Evidence from both yeast and mammalian experimental models suggest that changes in chromosome copy number can cause changes in dosage of the products of many genes located on aneuploid chromosomes. These effects on gene expression can alter the balanced stoichiometry of various protein complexes, causing perturbations of their functions. Therefore, phenotypic consequences of aneuploidy will include chromosomal instability if the balanced stoichiometry of protein machineries responsible for accurate chromosome segregation is affected enough to perturb the function. The degree of chromosomal instability will depend on specific karyotypic changes, which may be due to dosage imbalances of specific genes or lack of scaling between chromosome segregation load and the capacity of the mitotic system. We propose that the relationship between aneuploidy and chromosomal instability can be envisioned as a “vicious cycle”, where aneuploidy potentiates chromosomal instability leading to further karyotype diversity in the affected population.

Causes and consequences of protein folding stress in aneuploid cells

“…1). A similar concept has been invoked to explain the relationship between aneuploidy and chromosomal instability, 23 and we therefore suggest that several of the phenotypes of aneuploid cells may be self-reinforcing.…”

“…9,10,23 However, the mechanisms behind this have so far remained elusive. It is tempting to speculate that an underlying reason for the genomic instability of aneuploid cells is defective protein folding.…”

Behavior of replication origins in Eukaryota – spatio-temporal dynamics of licensing and firing

“…Insufficient DNA replication leads to failure in chromosome duplication and impacts their segregation during mitosis. 18,[59][60][61] As mentioned earlier, CFSs sites lack the excess origin mechanism that can compensate for slowed or stalled forks. As a result, incompletely duplicated chromosomes may form anaphase bridges.…”

“…15 The anaphase bridges, however, activate a mitotic checkpoint that inhibits mitosis progression until the problem is resolved or induce aneuploidy and chromosomal instability, as well as cell death. 61 On the other hand, in yeast, a process called adaptation has been described, which allows yeast cells to overcome mitotic arrest and continue cell division. 15 The phenomenon of genome chaos itself may be triggered by a single event or by a drug treatment (e.g., C-Frag or PCC).…”

Molecular bio-dosimetry for carcinogenic risk assessment in survivors of Bhopal gas tragedy

“…Environmental mutagenic agents, in this regard, can predispose and produce heritable chromosomal aberrations leading to unbalanced complements of chromosomes with varying degrees of severity. Such structural chromosomal rearrangements and losses/gains from non-disjunctions and multipolar mitoses are perceived to be the major factors for aneuploidy [57]. In our published studies, the ability of MIC to induce chromosomal instability was evident from the results obtained with cytogenetic analysis of treated B/CMBA.Ov, NCTC-1469, GC-1 spg, HEK-293, IMR-90 and FHC cells.…”