Telomere

Telomere - What are Telomeres?

A telomere is a region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from deterioration.

Russian theorist Alexei Olovnikov was the first to recognize (1971) the problem of how chromosomes could replicate right to the tip, as such was impossible with replication in a 5' to 3' direction. To solve this and to accommodate Leonard Hayflick's idea of limited somatic cell division, Olovnikov suggested that DNA sequences would be lost in every replicative phase until they reached a critical level, at which point cell division would stop.

During cell division, enzymes that duplicate the chromosome and its DNA cannot continue their duplication all the way to the end of the chromosome.

If cells divided without telomeres, they would lose the ends of their chromosomes, and the necessary information they contain. (In 1972, James Watson named this phenomenon the "end replication problem".)

The telomeres are disposable buffers blocking the ends of the chromosomes and are consumed during cell division and replenished by an enzyme, the telomerase reverse transcriptase.

They have been likened to the aglets (tips) on the ends of shoelaces that keep them from fraying.

In 1975–1977, Blackburn, working as a postdoctoral fellow at Yale University with Joseph Gall, discovered the unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends. Their work was published in 1978.

The telomere shortening mechanism normally limits cells to a fixed number of divisions, and animal studies suggest that this is responsible for aging on the cellular level and sets a limit on lifespans.

Telomeres protect a cell's chromosomes from fusing with each other or rearranging—abnormalities which can lead to cancer—and so cells are normally destroyed when their telomeres are consumed. Most cancers are the result of "immortal" cells which have ways of evading this programmed destruction.

Elizabeth Blackburn, Carol Greider, and Jack Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Telomere" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.

Telomere Shortening

Telomeres shorten in part because of the ''end replication problem'' that is exhibited during DNA replication in eukaryotes only.

Because DNA replication does not begin at either end of the DNA strand, but starts in the center, and considering that all DNA polymerases that have been discovered move in the 5' to 3' direction, one finds a leading and a lagging strand on the DNA molecule being replicated.

On the leading strand, DNA polymerase can make a complementary DNA strand without any difficulty because it goes from 5' to 3'. However, there is a problem going in the other direction on the lagging strand.

To counter this, short sequences of RNA acting as primers attach to the lagging strand a short distance ahead of where the initiation site was.

The DNA polymerase can start replication at that point and go to the end of the initiation site.

This causes the formation of Okazaki fragments. More RNA primers attach further on the DNA strand and DNA polymerase comes along and continues to make a new DNA strand.

Eventually, the last RNA primer attaches, and DNA polymerase, RNA nuclease and DNA ligase come along to convert the RNA (of the primers) to DNA and to seal the gaps in between the Okazaki fragments. But in order to change RNA to DNA, there must be another DNA strand in front of the RNA primer.

This happens at all the sites of the lagging strand, but it does not happen at the end where the last RNA primer is attached. Ultimately, that RNA is destroyed by enzymes that degrade any RNA left on the DNA. Thus, a section of the telomere is lost during each cycle of replication at the 5' end of the lagging strand.

However, in vitro studies (von Zglinicki et al. 1995, 2000) have shown that telomeres are highly susceptible to oxidative stress.

Telomere shortening due to free radicals explains the difference between the estimated loss per division because of the end-replication problem (ca. 20 bp) and actual telomere shortening rates (50-100 bp), and has a greater absolute impact on telomere length than shortening caused by the end-replication problem.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Telomere" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.

Systemic Telomere Length and Aging

As a measure of systemic telomere length, peripheral blood leukocyte telomere length is generally preferred. Systemic telomere length has been proposed as a marker of biological aging.

A subject's systemic telomere length is predominantly genetically determined, but has several other known determinants: age (shorter telomeres in older people), paternal age at birth (longer telomeres in subjects with older fathers at their birth) and sex (shorter telomeres in men, probably due to a faster telomere attrition).

Evidence suggests that elevated levels of oxidative stress and inflammation further increase the telomere attrition rate.

Vitamin D may have an effect on peripheral blood leukocyte telomere length. ''Richards and coworkers'' examined whether vitamin D concentrations would slow the rate of shortening of leukocyte telomeres.

The authors stated that vitamin D is a potent inhibitor of the proinflammatory response and slows the turnover of leukocytes. Leukocyte telomere length (LTL) predicts the development of aging-related disease, and the length of these telomeres decreases with each cell division and with increased inflammation.

Researchers measured serum vitamin D concentrations in 2160 women, aged 18–79 years (mean age: 49.4), from a large population-based cohort of twins.

This study divided the group into thirds, based on vitamin D levels, and found that increased age was significantly associated with shorter LTL (r = -0.40, P < 0.0001).

Higher serum vitamin D concentrations were significantly associated with longer LTL (r = 0.07, P = 0.0010) and this finding persisted even after adjustment for age (r = 0.09, P < 0.0001) and other variables that independently could affect LTL (age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity).

The difference in LTL between the highest and lowest tertiles of vitamin D was highly significant (P = 0.0009) and the authors stated that this was equivalent to 5.0 years of aging.

The authors concluded that higher vitamin D levels, easily modifiable through nutritional supplementation, were associated with longer LTL. This underscores the potentially beneficial effects of vitamin D on aging and age-related diseases.

Also, peer reviewed clinical studies indicate a relationship between regular exercise and the minimizing of telomere erosion in both mice and humans.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Telomere" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.

Telomeres and Cancer

As a cell begins to become cancerous, it divides more often and its telomeres become very short. If its telomeres get too short, the cell may die.

It can escape this fate by becoming a cancer cell and activating an enzyme called telomerase, which prevents the telomeres from getting even shorter.

Studies have found shortened telomeres in many cancers, including pancreatic, bone, prostate, bladder, lung, kidney, and head and neck.

Measuring telomerase may be a new way to detect cancer. If scientists can learn how to stop telomerase, they might be able to fight cancer by making cancer cells age and die.

In one experiment, researchers blocked telomerase activity in human breast and prostate cancer cells growing in the laboratory, prompting the tumor cells to die. But there are risks.

Blocking telomerase could impair fertility, wound healing and production of blood cells and immune system cells.

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 is active 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.

This article is licensed under the Creative Commons Attribution-ShareAlike License. It uses material from the Wikipedia article on "Telomere" All material adapted used from Wikipedia is available under the terms of the Creative Commons Attribution-ShareAlike License. Wikipedia® itself is a registered trademark of the Wikimedia Foundation, Inc.