The Role of Telomeres in Genomic Instability

Abstract

summaryGenomic instability is now considered to play an important role in promoting the genetic changes necessary for cancer. It has been reported that exposure of cells to ionizing radiation or chemical agents can promote genomic instability, although the mechanisms involved are not understood. Knowledge concerning mechanisms of genomic instability has been derived from studies in yeast and human genetic disease, where mutations in a variety of genes involved in DNA replication, repair, and cell cycle regulation have been found to promote genomic instability. However, the identity of the mechanisms responsible for the genomic instability common to many cancer cells has yet to be determined, although increasing evidence demonstrates that loss of telomere function is important in this process. Telomeres are nucleoprotein structures that serve as caps that protect the ends of chromosomes and are maintained by the enzyme telomerase. Telomeres are maintained in the germ line but shorten with age in most somatic cells due to the lack of sufficient telomerase. This telomere shortening serves as a signal for replicative cell senescence, which protects against the unlimited cell division required for advanced forms of cancer. As a result, malignant cancer cells invariably maintain their telomeres, which is necessary to prevent massive chromosome fusion and cell death. However, telomere loss can occur during “crisis,” in which cells that fail to senesce undergo critical telomere shortening prior to re-establishing the ability to maintain telomeres. In addition, it is now clear that even tumor cells that maintain telomeres continue to show a high rate of telomere loss, suggesting a fundamental defect in telomere maintenance in many cancer cells. Telomere loss results in sister chromatid fusion that initiates prolonged breakage/fusion/bridge (B/F/B) cycles, in which chromosomes repeatedly fuse and break for many cell generations. This prolonged instability results in various chromosomal rearrangements that are commonly associated with cancer, including amplification, deletions, nonreciprocal translocations, and duplications of whole chromosome arms. This instability is not confined to the chromosome that originally lost its telomere but can be transferred to other chromosomes as well. Thus, the loss of a single telomere can result in a large population of cells with a variety of changes in many different chromosomes. Understanding the mechanisms of telomere loss and the factors that control chromosome instability resulting from B/F/B cycles is therefore an important goal in cancer research.