Review
Mechanisms leading to chromosomal instability

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Abstract

Chromosomal instability is a common feature of cancer cells. Several cellular mechanisms lead to numerical and structural chromosomal instability in cancer cells, including defects in chromosomal segregation, cellular checkpoints that guard against reproduction of abnormal cells, telomere stability, and the DNA damage response. Human papillomavirus interferes with these processes, causing chromosomal instability and tumor formation in some of the epithelial cells which it infects. The rate of discoveries about the mechanisms leading to chromosomal instability in cancer cells is increasing rapidly. Although these mechanisms were thought to be unrelated, they are intimately intertwined, connecting the complex network of cellular pathways. Since chromosomal instability is undoubtedly a major cause of tumor evasion of therapy, understanding the mechanisms leading to chromosomal instability has major translational significance.

Introduction

Chromosomal instability is the gain and/or loss of whole chromosomes or chromosomal segments at a higher rate in a population of cells, such as cancer cells, compared to normal cells. Numerical and structural chromosomal alterations and chromosomal instability are common features of human tumors. In most cases, aneuploidy results from the numerical chromosomal alterations. Further segmental chromosomal gains and losses come from structural chromosomal alterations, including reciprocal and non-reciprocal translocations, homogeneously staining regions, amplifications, insertions, and deletions. Structural alterations may result in a further imbalance in gene expression, resulting in chromosomal instability. In some tumors, each cell within the tumor has a different karyotype due to chromosomal instability, which can be defined in practical terms as numerical and/or structural chromosomal alterations that vary from cell to cell. Chromosomal instability is thought to be the means by which cells develop the features that enable them to become cancer cells [1]. In spite of the presence of cell-to-cell chromosomal instability, the tumor karyotype is quite stable over time, probably because advanced tumors have evolved a genotype optimized for growth, making it less likely that additional genetic alterations will confer an additional growth advantage [2]. Chromosomal alterations and karyotypic instability in human tumor cells have been investigated for nearly a century. Theodor Boveri, while studying chromosomal segregation in Ascaris worms and Paracentrotus sea urchins in the early 1900s suggested that malignant tumors arise from a single cell with an abnormal genetic constitution acquired as a result of defects in the mitotic spindle apparatus [3]. Boveri was right; the best explanation today is that numerical chromosomal instability appears to arise as a result of chromosome segregational defects [4], [5], [6], [7], most frequently resulting from multipolar spindles as discussed in Section 2. Structural chromosomal instability results from chromosome breakage and rearrangement due to defects in cell cycle checkpoints, the DNA damage response and/or loss of telomere integrity [8], [9]. Structural chromosomal instability frequently results from breakage-fusion-bridge (BFB) cycles, first described in maize by geneticist Barbara McClintock in 1938 ([10] reviewed in [11]). In this process, a chromatid break occurs, exposing an unprotected chromosomal end which, after replication, is thought to fuse with either another broken chromatid or its sister chromatid to produce a dicentric chromosome. During the anaphase stage of mitosis, the two centromeres are pulled to opposite poles, forming a bridge which breaks, resulting in more unprotected chromosomal ends, and thus the cycle continues [12]. Our recent studies of oral cancer cells suggest that structural chromosomal instability, including gene amplification, occurs by BFB cycles [6], [13], [14]. The basis for these BFB cycles is not entirely clear, although recent studies of telomere mechanics and the DNA damage response suggest that these two critical cellular processes play major roles in the development of structural chromosomal instability. Thus, the processes of chromosomal segregation, telomere function, and the DNA damage response and their role in mechanisms leading to chromosomal instability are introduced in this review. A selected list of genes and their proteins involved (or potentially implicated) in pathways leading to chromosomal instability is presented in Table 1.

Section snippets

Chromosome segregational defects as a mechanism leading to chromosomal instability

One of the fundamental processes required in the life of a cell, whether from a unicellular or multicellular organism, is chromosome segregation. Fidelity of chromosome segregation, whether in meiosis or mitosis, is necessary for genomic stability and the continuation of life as we know it. Aberrations in the process of chromosome segregation result in aneuploidy, abnormal numbers of chromosomes being distributed to daughter cells, such that the daughter cells do not match each other or their

A defective DNA damage response as a mechanism leading to chromosomal instability

For many years, cytogeneticists have known that patients with ‘chromosome breakage’ syndromes express chromosomal instability. Yet, until recently, features of these syndromes have not been utilized to define defects in the DNA damage response in cancer cells. Causes of DNA damage include attack by ultraviolet light, ionizing radiation, or environmental mutagens and cellular errors, such as base pair mismatch during DNA replication, replication fork collapse, or defects caused by naturally

Telomere dysfunction as a mechanism leading to chromosomal instability

O’Hagan et al. [45] presented evidence that telomere dysfunction is a cause of chromosomal instability. These investigators used array-CGH to examine chromosomal gains and losses in mTerc−/−, p53+/− mice and found that telomere dysfunction results in segmental gains and losses that drive epithelial carcinogenesis in the mouse model. Further, they found that the alterations mirror those in human epithelial tumors, lending support to the hypothesis that telomere-based crisis and associated

Chromosomal instability leads to loss of heterozygosity (and further chromosomal instability)

Recent studies from the Lengauer laboratory [23], [49], [86], [87] are based on the idea that specific genetic defects in a large proportion of human tumors lead to chromosomal instability as a result of an increased rate of loss of heterozygosity and that these events can occur prior to malignant conversion. These authors also provide a mathematical framework for investigating the effects of chromosomal instability on the development and evolution of cancer cells [86]. Further, by examining

Cell cycle disturbances result in chromosomal instability

Many of the mechanisms leading to chromosomal instability discussed above result in disturbances in cell cycle checkpoint function. This topic is so vast that it merits its own review. In the context of this review, however, suffice it to say that several different cell cycle disturbances have been reported to play a role in chromosomal instability. Minhas et al. [56] reported defects in the spindle assembly checkpoint, which may contribute to the chromosomal instability in head and neck cancer

Human papillomavirus drives chromosomal instability by multiple mechanisms

The oncogenic types of human papillomavirus (HPV) illustrate how a virus can interfere with several of the processes discussed in this review and lead to chromosomal instability (recently reviewed by Duensing and Münger [90]). HPV alters chromosomal segregation, the DNA damage response, telomere behavior, and cell cycle checkpoint regulation. Veldman et al. [91] showed that the HPV E6 protein interacts with the MYC protein to activate the hTERT promoter, leading to cellular telomerase activity.

Summary

In summary, defects in chromosome segregation, centrosome dynamics, telomere mechanics, the DNA damage response, cell cycle regulation, and cell cycle checkpoints may play important roles in the development and maintenance of chromosomal instability, the primary impact of which is cancer. Chromosomal instability is most likely one of the most common causes of tumor cell evasion of therapy. Therefore, a complete understanding of the biological basis of chromosomal instability is essential for

Acknowledgements

The author is grateful to her collaborators, especially William S. Saunders, and her past and present trainees for challenging current concepts and stimulating hearty discussions on the mechanisms leading to chromosomal instability. Thanks to Drs. Janet D. Rowley and Bob Ferrell for encouragement, support, and helpful discussions over the years. The author thanks Drs. John Petrini, Stefan Duensing, Christoph Lengauer, and Bill Brinkley for helpful discussions during manuscript preparation. The

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