Telomeres in Cell Function: Cancer and Ageing

Telomeres, dynamic structures capping the ends of chromosomes, are composed of long arrays of repeated deoxyribonucleic acid (DNA) sequences accompanied by closely associated proteins. In most organisms, these repeats are maintained by the enzyme, telomerase. Telomeres were long thought to do no more than assure the physical integrity of chromosome ends. It is now recognized that telomere activity includes involvement with genomic replication, repair and maintenance machinery. Telomeres predate multicellular organisms, and their length regulation evolved differently in widely separated lineages; in humans, telomerase is inactivated in most somatic cells and, therefore, telomeres shorten with age. Telomeres play important roles in assuring genetic material is partitioned equally in cell division, in activating tumour-suppressor genes in ageing tissue and in epigenetically regulating nearby subtelomeric genes for rapid response to the environment. With these involvements in fundamental cellular machinery, telomeres are more than bystanders in the cellular processes of ageing and cancer. Key Concepts Telomeres, which cap the ends of chromosomes, are composed of long arrays of repeated DNA sequences and closely associated proteins. Telomeres are thought to have evolved to protect faithful genome replication as cells acquired large genomes, cellular nuclei and multiple chromosomes. Telomere-associated proteins include some that are central to the repair of broken chromosomes and to the cell cycle checkpointing that prevents cells with nonviable broken chromosomes from propagating. In most organisms, telomere repeats are maintained by the enzyme, telomerase, which replaces the few terminal nucleotides that are lost at each cycle of DNA replication, as well as nucleotides lost to enzymatic degradation. Lost sequences are replaced by copying from the enzyme's RNA component. Telomere and telomerase activities are varied and important in many aspects of the control of cellular replication. Telomeres prevent the cell from treating chromosome ends as broken chromosomes. They help to ensure equal distribution of genetic material into each gamete at meiosis. They are involved in regulating the expression of highly variable subtelomeric genes in response to environmental changes. The full range of telomere and telomerase activities has not yet been explored but, given what we already know, these activities must be tightly controlled for the safety of the cell. In organisms from yeast to humans the loss of telomerase activity leads to telomere shortening and eventually to replicative senescence. Given their intimate involvement in cellular replication, telomeres and telomerase appear to have been frequently coopted in evolving controls for pathogenic genomic replication. These controls have evolved differently in different organisms, although all conserve the basic mechanism of telomere maintenance. Telomerase must be active in certain cell types like germline cells, to ensure that gametes carry complete telomeres, and in epithelial and blood cells that turn over very rapidly. In humans, telomerase activity is turned off in many somatic cells, although this restricts the number of cell divisions of these cells and contributes to senescence. This regulation is believed to have evolved as a protection against telomerase going wild and leading to cancer. In yeast telomerase is normally active in all cells. Keywords: cancer and ageing; chromosomes; DNA replication; telomeres; telomerase