Dr Jekyll and Mr Hyde: role of aneuploidy in cellular adaptation and cancer
Introduction
Genomic instability has been a central issue in several basic fields of cell biology for the past decades, spanning from growth and cell cycle regulation, mitosis and meiosis, to cancer progression. Among the main products of genomic instability, and especially of chromosome instability, are DNA copy number changes that often involve relatively large chromosomal regions and in some cases span entire chromosomes. For the scope of this review, we will hereafter refer to segmental and whole-chromosome copy number changes collectively as ‘aneuploidy’. Tremendous efforts have been devoted to the elucidation of the mechanisms leading to aneuploidy (comprehensively reviewed in [1, 2]). We only emphasize here that there is a wide variety of roads that could lead to aneuploidy. Perturbations in components of the chromosome segregation machinery, in the spindle assembly checkpoint, in the S-phase checkpoint, as well as in homologous and non-homologous recombination pathways are some of the common causes leading to either segmental or whole-chromosome aneuploidy [1, 2]. With so many different doors open to aneuploidy, frequent observation of this mutation comes with no surprise. In fact, aneuploidy has long been observed in many different organisms and contexts (Table 1). This article focuses on the consequences of aneuploidy at the cellular level, which has been debated in at least two different but related contexts.
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Debates on aneuploidy
Since most cancer cells are aneuploid, one debate has centered on whether aneuploidy is a cause or a consequence of cancer [3, 4]. As cancer cells are often defective in one or more cellular machineries that ensure genome integrity and stability, it is natural to think of aneuploidy as a, perhaps innocent, byproduct of the cellular transformation process itself [5]. The opposing argument is that, based on the view that cancer is a Darwinian process where cells are selected to overcome severe
Aneuploidy affects gene expression on multiple levels
An important question to answer in order to resolve the above debated issues is whether aneuploidy has phenotypic consequences, that is, whether it is ‘innocent’ or ‘guilty’ of causing phenotypic changes, and if the answer is yes, then what might the consequences be with respect to fitness or cancer progression. Evidence gathered in recent years across different organisms unequivocally suggests that changes in gene copy numbers caused by aneuploidy directly lead to changes in the level of mRNA
Aneuploidy profoundly affects the cellular phenotype
Despite a lack of conclusive demonstration on how aneuploidy may affect gene expression at the proteome level, evidence abounds that aneuploidy can bring about large changes in cellular phenotypes. Below we discuss several mechanisms by which aneuploidy affects phenotypic adaptation.
Conclusion and resolving the debates on aneuploidy
On the basis of the many ways by which aneuploidy can bring about phenotypic changes as discussed above, aneuploidy can be viewed as a large-effect mutation, through which large phenotypic leaps can be achieved in a single mutational step. In the classical theory of evolutionary adaptation, species are conceptualized as hikers on a fitness landscape that are trying to reach the nearest fitness peak through accumulation of a series of small-effect mutations [36] (Figure 2). In situations where
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
This work is supported by NIH grant RO1GM059964 to RL.
References (45)
- et al.
Mechanisms of chromosomal instability
Curr Biol
(2010) - et al.
Does aneuploidy cause cancer?
Curr Opin Cell Biol
(2006) - et al.
The hallmarks of cancer
Cell
(2000) - et al.
On the karyotypic origin and evolution of cancer cells
Cancer Genet Cytogenet
(2009) - et al.
High rates of “unselected” aneuploidy and chromosome rearrangements in tel1 mec1 haploid yeast strains
Genetics
(2008) - et al.
Proliferation of aneuploid human cells is limited by a p53-dependent mechanism
J Cell Biol
(2010) - et al.
Chromosomal variation in neurons of the developing and adult mammalian nervous system
Proc Natl Acad Sci U S A
(2001) - et al.
Genome instability: a mechanistic view of its causes and consequences
Nat Rev Genet
(2008) When theories collide: experts develop different models for carcinogenesis
J Natl Cancer Inst
(2001)- et al.
Derivation of human tumor cells in vitro without widespread genomic instability
Cancer Res
(2001)
The clonal evolution of tumor cell populations
Science
Cancer as an evolutionary and ecological process
Nat Rev Cancer
Origin of multidrug resistance in cells with and without multidrug resistance genes: chromosome reassortments catalyzed by aneuploidy
Proc Natl Acad Sci U S A
The chromosomal basis of cancer
Cell Oncol
Chromosome instability, chromosome transcriptome, and clonal evolution of tumor cell populations
Proc Natl Acad Sci U S A
Chromosomal instability determines taxane response
Proc Natl Acad Sci U S A
Aneuploidy and isochromosome formation in drug-resistant Candida albicans
Science
Formation of new chromosomes as a virulence mechanism in yeast Candida glabrata
Proc Natl Acad Sci U S A
Characteristic genome rearrangements in experimental evolution of Saccharomyces cerevisiae
Proc Natl Acad Sci U S A
The repertoire and dynamics of evolutionary adaptations to controlled nutrient-limited environments in yeast
PLoS Genet
Widespread aneuploidy revealed by DNA microarray expression profiling
Nat Genet
Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor
Cell
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