Difference between revisions of "Telomere shortening"

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Latest revision as of 09:26, 2 August 2015

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Telomere shortening

Telomeres, the non-coding sequences DNA-protein structures at the ends of chromosomes, in the absence of telomerase, progressively shorten with each cell division. Telomeres are the physical ends of linear chromosomes. In mammals, telomeres are composed of a variable number of tandem repeats of DNA that are made up of (TTAGGG)n repeats. Although the bulk of telomeric DNA is double stranded, the extreme terminus is a single-stranded G-rich 3¢ overhang that serves as a template for elongation and forms a telomeric `T-loop'. This loop is stabilized by certain telomerebinding proteins, notably TRF1 and TRF2. The functions of telomeres appear to include protection of chromosomes from illegitimate fusion, the localization of chromosomes in the nucleus and the selective silencing of proximal subtelomeric genes. The telomeric repeat sequences are added on by the enzyme telomerase, which, when present, compensates for the loss of DNA from the end of chromosomes due to incomplete replication.

One reason for telomere shortening is the so-called “end replication problem”: during the replication of the lagging strand, the RNA primer for the most distal Okazaki fragment cannot be replaced by DNA. Accordingly, the newly synthesized lagging strand is shorter by at least the length of the primer (less than 12 nt), resulting in an overhang of the parental G-rich strand at one end of the chromosome. Experimentally, G-rich overhangs 100–500 nt long have been found. On the basis of regular shortening, telomeres have been connected with replicative aging in vitro and in vivo and were characterized as a “mitotic clock”. Direct evidence linking telomere shortening causally to replicative senescence was given by overexpression of the telomere-elongating enzyme, telomerase, in mortal cells.

TheTRF2 complex has a fundamental role in protecting the telomeric single-stranded G-rich overhang from degradation and from DNA repair activities, thereby preventing telomere end-to-end fusions. Interestingly, a number of DNA repair proteins that are involved in several repair pathways localize to telomeres, and some of them do so through a direct interaction with TRF2.

In humans, both in vivo and in vitro, telomere shortening appears to be a major component of cell senescence and ageing. An age-dependent telomere shortening has been demonstrated in different self-renewing human tissues like peripheral blood monocytes, fibroblasts, endothelial cells, and others. The variation of telomere length between different individuals seems to be mainly genetically determined. The involvement of telomeres has been implicated in several conditions: progeria, Werner syndrome, and hyper- and hypoproliferative diseases. Short telomeres are characteristic of human diseases of various origins that are associated with ageing, such as heart disease, ulcerative colitis, liver cirrhosis and atherosclerosis, as well as several premature ageing syndromes (for example, dyskeratosis congenita).