Wednesday, October 7, 2009
Telomeres are sequences at the ends of chromosomes. Though they are written in the 'alphabet' of the genes, telomeres do not contain the codes for proteins. So telomeres are not themselves genes, but neither are they meaningless junk. Instead these repetitive sequences protect the ends of the chromosome from damage, and prevent the chromosomes from fusing into rings, or binding haphazardly to other DNA in the cell nucleus.
Cells with critically short telomeres alter their character by transcribing a partly distinct set of genes. They also become unresponsive to triggers that would normally stimulate them to divide. Though these growth arrested cells can live on in the body for years, once they have reached this state, they do not under normal circumstances, replicate themselves. They are said to have reached their Hayflick limit (named for the discoverer of the arrested state).
Because sperm and egg cells are themselves descended from progenitor cells, if there were no mechanism for replacing lost telomere, then all organisms with linier chromosomes (eukaryotes) would be condemned to quick extinction due to Hayflick limits in their reproductive tissues. Clearly, that's not the case. Instead, there are a number of mechanisms in nature that counteract the natural tendency of telomeres to erode over time. Vertebrates, including mammals, use a remarkable enzyme dubbed 'telomerase'. This hybrid molecule, part protein, part RNA, is capable of slowing telomere erosion, halting erosion altogether, or lengthening telomeres beyond those in the parent cell. The genes that produce telomerase are found in every potentially replicating cell in the body, including cells at their Hayflick limits, but the genes that produce telomerase are inactive in the great majority of our cells, for the vast bulk of our lives. Those genes are active across the body only in early fetal development. After that point, telomerase is only found in a few special tissues such as antibody producing immune cells, cells that replenish the gut lining, and sperm producing cells
Telomeres and cancer
Cancer cells require a mechanism to maintain their telomeric DNA in order to continue dividing indefinitely (immortalization). A mechanism for telomere elongation or maintenance is one of the key steps in cellular immortalization, and can be used as a diagnostic marker in the clinic. Telomerase, the enzyme complex responsible for elongating telomeres, is activated in approximately 90% of tumors. However, a sizeable fraction of cancerous cells employ alternative lengthening of telomeres (ALT), a non-conservative telomere lengthening pathway involving the transfer of telomere tandem repeats between sister-chromatids. The mechanism by which ALT is activated is not fully understood because these exchange events are difficult to assess in vivo.
Telomerase is the natural enzyme which promotes telomere repair. It is however not active in most cells. It certainly is active though in stem cells, germ cells, hair follicles and in 90 percent of cancer cells. Telomerase functions by adding bases to the ends of the telomeres. As a result of this telomerase activity, these cells seem to possess a kind of immortality.
Studies using knockout mice have demonstrated that the role of telomeres in cancer can both be limiting to tumor growth, as well as promote tumorigenesis, depending on the cell type and genomic context.
If telomeres become too short, they will potentially unfold from their presumed closed structure. It is thought that the cell detects this uncapping as DNA damage and will enter cellular senescence, growth arrest or apoptosis depending on the cell's genetic background (p53 status). Uncapped telomeres also result in chromosomal fusions. Since this damage cannot be repaired in normal somatic cells, the cell may even go into apoptosis. Many aging-related diseases are linked to shortened telomeres. Organs deteriorate as more and more of their cells die off or enter cellular senescence