ReviewMechanisms leading to chromosomal instability
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
References (96)
- et al.
The hallmarks of cancer
Cell
(2000) - et al.
The mitotic machinery as a source of genetic instability in cancer
Semin Cancer Biol
(1999) - et al.
Take care of your chromosomes lest cancer take care of you
Cancer Cell
(2003) - et al.
Aurora kinases link chromosome segregation and cell division to cancer susceptibility
Curr Opin Genet Dev
(2004) - et al.
Dual roles of human BubR1, a mitotic checkpoint kinase, in the monitoring of chromosomal instability
Cancer Cell
(2003) - et al.
ATR regulates fragile site stability
Cell
(2002) - et al.
BRCA2 is required for homology directed repair of chromosomal breaks
Mol Cell
(2001) - et al.
Role of BRCA2 in control of the RAD51 recombination and DNA repair protein
Mol Cell
(2001) - et al.
Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways
Cell
(2002) - et al.
Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors
Cell
(2003)
H2AX haploinsufficiency modifies genomic stability and tumor susceptibility
Cell
The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder
Cell
The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response
Cell
Telomere dysfunction provokes regional amplification and deletion in cancer genomes
Cancer Cell
A critical role for Pin2/TRF1 in ATM-dependent regulation
J Biol Chem
The occurrence of chromosome segregational defects is an intrinsic and heritable property of oral squamous cell carcinoma cell lines
Cancer Genet Cytogenet
AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol
Cancer Cell
Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons
Cell
A p53-dependent checkpoint pathway prevents rereplication
Mol Cell
Cancer genetics in oncology practice
Ann Oncol
Cancer incidence in persons with Fanconi anemia
Blood
Chromosome aberrations in solid tumors
Nat Genet
The origin of malignant tumors, by Theodor Boveri … translated by Marcella Boveri
Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation
Nat Genet
Chromosomal instability and cytoskeletal defects in oral cancer cells
Proc Natl Acad Sci USA
Centrosome amplification drives chromosomal instability in breast tumor development
Proc Natl Acad Sci USA
Telomere dysfunction and the initiation of genome instability
Nat Rev Cancer
The fusion of broken ends of sister half-chromatids following chromatid breakage at meiotic anaphases
Mo Agric Exp Station Res Bull
Chromosome organization and genic expression
Cold Spring Harbor Symp Quant Biol
Spontaneous alterations in chromosome size and form in Zea mays
Cold Spring Harbor Symp Quant Biol
A consistent pattern of RIN1rearrangements in oral squamous cell carcinoma cell lines supports a breakage-fusion-bridge cycle model for 11q13 amplification
Genes Chromosomes Cancer
High-resolution mapping of the 11q13 amplicon and identification of a gene, TAOS1, that is amplified and overexpressed in oral cancer cells
Proc Natl Acad Sci USA
The cellular geography of Aurora kinases
Nat Rev Mol Cell Biol
A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers
EMBO J
Aurora B couples chromosomal alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores
J Cell Biol
The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint
J Cell Biol
Mutations of mitotic checkpoint genes in human cancers
Nature
Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts
Cancer Res
Three classes of genes mutated in colorectal cancers with chromosomal instability
Cancer Res
Human Zw10 and ROD are mitotic checkpoint proteins that bind to kinetochores
Nat Cell Biol
MAD2 and p53 expression profiles in colorectal cancer and its clinical significance
World J Gastroenterol
Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells
Proc Natl Acad Sci USA
ATM and related protein kinases: safeguarding genome integrity
Nat Rev Cancer
Ataxia-telangiectasia
Adv Exp Med Biol
Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest
Nat Genet
Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability
Molec Cell Biol
Localization by Q-banding of mitotic chiasmata in cases of Bloom's syndrome
Chromosoma
Enhanced tumor formation in mice heterozygous for Blm mutation
Science
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