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Cellular Aging: Telomeres

Telomeres, Genome Stability, And Cancer

The hallmark of telomeres is their ability to confer stability on chromosome ends and prevent chromosome ends from activating the cellular surveillance mechanisms protecting cells from the deleterious effects of DNA breaks. Chromosomes with critically short telomeres become compromised in chromosome-end stability, and, because telomeres are generally shorter in tumors than in adjacent healthy tissue, it was suggested that telomere dysfunction could contribute to tumorigenesis by increasing genomic instability. In the short term, this genomic instability might promote tumor formation by allowing growth-advantageous mutations (i.e., mutations that permit cells to remain viable under conditions when, normally, the cells would die) to accumulate rapidly. However, this scenario requires that the cellular mechanism(s) that normally monitor telomere length and prevent cells with critically short telomeres from dividing be blocked. Under these conditions, cells with critically short telomeres would continue dividing. These cells would enter a period of extreme chromosomal instability. Eventually, however, such rampant genome instability might prove deleterious to tumor survival by generating mutations in genes that are essential for cellular survival. Thus, stabilization of the genome, perhaps through activation of telomerase, would have a selective advantage. Experiments carried out by the DePinho and Greider groups utilizing telomerase-deficient mice support the idea that transient telomere malfunction may promote tumorigenesis.

Figure 4 Summary of the link between telomere length, replicative senescence, and tumorigenesis. In the germ line, telomerase is active and telomere length is stable. In somatic cells, telomerase is not active. As a result, telomeres become shorter with each division until a critical length is reached and the cells undergo replicative senescence. If this process is bypassed through mutation of regulating proteins, the cells will continue to divide until telomere function is lost. This results in a period of genome instability, which possibly promotes tumorigenesis through hypermutation. Reactivation of telemorase permits maintenance of telomeric DNA conferring immortality and genome stabilization. SOURCE: Greider, Carol. ``Mammalian Telomere Dynamics: Healing, Fragmentation, Shortening, and Stabilization.'' Current Opinion in Genetics and Development 4 (1994): 203-211.

Additional topics

Medicine EncyclopediaAging Healthy - Part 1Cellular Aging: Telomeres - Telomeres Are Chromosome Caps, Telomere Structure, Telomeres And Replication, Telomeres And Replicative Senescence, Telomeres And Premature Aging Syndromes