Telomeres and chromosome instability
Section snippets
The role of telomeres in maintaining chromosome stability
Genomic instability has been proposed to play an important role in cancer by accelerating the accumulation of genetic changes responsible for cancer cell evolution [1], [2]. Genomic instability can occur through a variety of mechanisms, including a defective response to DNA damage, a defect in DNA replication, or a defect in chromosome segregation. The importance of some of these mechanisms has been demonstrated through the study of human genetic diseases that demonstrate both increased
Mechanisms of telomere loss
Loss of telomere function leading to chromosome fusion can occur through a variety of mechanisms, involving either endogenous events or exogenous DNA damage. Chromosome fusion can result from the loss of capping function when telomeric repeat sequences are still present, or through the loss of sufficient telomeric repeat sequences to maintain a functional telomere. Loss of capping function has been demonstrated to occur in cells deficient in a number of telomere-associated proteins, including
The role of telomere loss in chromosome instability in cancer
Chromosome rearrangements resulting from telomere loss in cancer have been proposed to result primarily from the extensive chromosome fusion that occurs when telomeres become critically short during crisis [38], [39]. However, telomere loss is not confined to cells in crisis, since many early passage human tumor cells [40] and cell lines [33], [41], [42] demonstrate telomere instability, as well as anaphase bridges, an indicator of chromosome fusion. Telomere instability is also nearly
The role of cell cycle checkpoints in preventing B/F/B cycles
The above studies with telomerase deficient mice [38], [39] demonstrate that a defect in p53-mediated cell cycle checkpoints or apoptosis is required to observe chromosome instability involving B/F/B cycles. Similar results were obtained with mice deficient in NHEJ, which also only demonstrate increased cancer involving B/F/B cycles in a p53-deficient background [52]. In addition, chromosome instability as a result of dsb-induced telomere loss occurs in mouse embryonic stem (ES) cells, which
DNA amplification involving B/F/B cycles
One of the most well characterized types of rearrangements resulting from B/F/B cycles is gene amplification, an important rearrangement in human cancer [58], [59]. The role of B/F/B cycles in gene amplification has been extensively studied in hamster cells [60], [61], [62], [63]. However, the analysis of highly amplified genes in human cells has often failed to demonstrate structures consistent with B/F/B cycles. Instead, highly amplified genes in human cancer are commonly found on
Mechanisms of telomere restoration
As originally proposed by McClintock from her studies in maize [49], the addition of a telomere on to the end of a broken chromosome can prevent or terminate B/F/B cycles. In yeast and Tetrahymena, broken chromosomes can be “healed” by the de novo addition of telomeric repeat sequences by telomerase [71], [72]. This chromosome healing by telomerase in yeast is carefully regulated, and occurs preferentially near telomeric repeat sequences within the chromosome that may serve as nucleation sites
Consequences of telomere loss in yeast
The use of selectable marker genes has proven to be a valuable tool in the study of the types of events associated with telomere loss. In yeast that are deficient in dsb repair, the loss of a telomeric marker gene often involves de novo telomere addition on to the end of the broken chromosome [71], [74], [83]. Terminal deletions resulting from de novo telomere addition were also found to be the most frequent type of gross chromosome rearrangement observed in yeast deficient in proteins involved
The use of selectable marker genes for monitoring telomere loss in mammalian cells
Similar to studies in yeast, selectable marker genes near the ends of chromosomes have been used to study the consequences of telomere loss in mammalian cells [89]. This approach has the advantage of following the changes in individual chromosomes from the event initiating instability, rather than attempting to reconstruct the sequence of events involved in the generation of complex rearrangements, as is often the case in studies of chromosomal instability. A Herpes simplex virus thymidine
Mechanisms of telomere acquisition during B/F/B cycles
The prolonged B/F/B cycles in the EJ-30 human tumor cell line provided an excellent opportunity to characterize the types of events involved in telomere acquisition and chromosome stabilization. The analysis of 297 metaphase spreads from a subclone undergoing B/F/B cycles on the marker chromosome after selection for loss of a telomere demonstrated that telomere acquisition occured through a variety of mechanisms [50], [89]. The most common mechanism for telomere acquisition was through the
Transfer of amplified regions to other chromosomes
The B/F/B cycles resulting from telomere loss can result in the transfer of amplified regions from one chromosome to another [42]. This transfer of amplified regions could account for the observation that amplified genes in human cancer cells are commonly found at sites other than where the endogenous genes are initially located. One mechanism for the transfer of amplified regions is through the formation of DM chromosomes. As mentioned earlier, regions amplified by B/F/B cycles in human cells
Failure of telomere addition to prevent B/F/B cycles
An important observation from the above studies is that despite the fact that cancer cells are able to maintain telomeres and express telomerase activity, they are not capable of preventing B/F/B cycles through the direct addition of a new telomere on to the end of a broken chromosome. Twenty five percent of the telomeres that were acquired during B/F/B cycles occurred without detectable translocations or duplications. However, most of these new telomeres may have resulted from translocations
Conclusion
As pointed out above, it is becoming increasingly clear that telomere loss plays an important role in the chromosome instability commonly associated with cancer. Importantly, this instability is not limited to crisis, when telomeres become critically short in cells that fail to senesce. Cancer cells that maintain telomeres sufficiently well to escape crisis continue to show an increased rate of telomere loss, demonstrating that they commonly have a fundamental defect that promotes telomere
Acknowledgements
This work was supported by National Institute of Environmental Health Science Grant No. RO1 ES008427 and National Cancer Institute Grant No. RO1 CA69044.
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