TERT is a reverse transcriptase, which is a class of enzyme that creates single-stranded DNA using single-stranded RNA as a template. Enzymes of this class (not TERT specifically, but the ones isolated from viruses) are utilized by scientists in the molecular biological process of Reverse Transcriptase PCR (RT-PCR), which allows the creation of several DNA copies of a target sequence using RNA as a template. As stated above, TERT carries its own template around, TERC.
By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-TTAGGG (in all vertebrates, the sequence differs in other organisms) to the 3' strand of chromosomes. These TTAGGG repeats (with their various protein binding partners) are called telomeres. The template region of TERC is 3'-CAAUCCCAAUC-5'. This way, telomerase can bind the first few nucleotides of the template to the last telomere sequence on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go, realign the new 3'-end of telomere to the template, and repeat the process. (For an explanation on why this elongation is necessary see Telomere shortening.)
The enzyme telomerase allows for replacement of short bits of DNA known as a telomere, which are otherwise lost when a cell divides via mitosis.
In normal circumstances, without the presence of telomerase, if a cell divides recursively, at some point all the progeny will reach their Hayflick limit. With the presence of telomerase, each dividing cell can replace the lost bit of DNA, and any single cell can then divide unbounded. While this unbounded growth property has excited many researchers, caution is warranted in exploiting this property, as exactly this same unbounded growth is a crucial step in enabling cancerous growth.
Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed in cells that need to divide regularly (e.g., in the immune system), whereas most somatic cells express it only at very low levels in a cell-cycle dependent manner.
A variety of premature aging syndromes are associated with short telomeres. These include Dyskeratosis congenita, Werner syndrome, Ataxia telangiectasia, Bloom syndrome, Fanconi anemia, Nijmegen breakage syndrome, and ataxia telangiectasia-like disorder. The genes that have been mutated in these diseases all have roles in the repair of DNA damage, and their precise roles in maintaining telomere length are an active area of investigation. While it is currently unknown to what extent telomere erosion contributes to the normal aging process, maintenance of DNA in general and telomeric DNA specifically, have emerged as major players. Dr. Michael Fossel has suggested in an interview that telomerase therapies may be used not only to combat cancer but also to actually get around human aging and extend lifespan significantly. He believes human trials of telomerase-based therapies for extending lifespan will occur within the next 10 years. This timeline is significant because it coincides with the retirement of Baby Boomers in the United States and Europe
With the activation of telomerase, some types of cells and their offspring become immortal, that is, their chromosomes will not become unstable no matter how many cell divisions they undergo (they bypass the Hayflick limit), thus avoiding cell death as long as the conditions for their duplication are met. Many cancer cells are considered 'immortal' because telomerase activity allows them to divide virtually forever, which is why they can form tumors. A good example of cancer cells' immortality is HeLa cells, which have been used in laboratories as a model cell line since 1951. They are indeed immortal - daily production of HeLa cells is estimated at several tons even up to this day.
While this method of modeling human cancer in cell culture is effective and has been used for many years by scientists, it is also very imprecise. The exact changes that allow for the formation of the tumorigenic clones in the above-described experiment are not clear. Scientists have subsequently been able to address this question by the serial introduction of several mutations present in a variety of human cancers. This has led to the elucidation of several combinations of mutations that are sufficient for the formation of tumorigenic cells, in a variety of cell types. While the combination varies depending on the cell type, a common theme is that the following alterations are required: activation of TERT, loss of p53 pathway function, loss of pRb pathway function, activation of the Ras or myc proto-oncogenes, and aberration of the PP2A protein phosphatase. That is to say, the cell has an activated telomerase, eliminating the process of death by chromosome instability or loss, absence of apoptosis-induction pathways, and continued activation of mitosis.
This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors that have not activated TERT, most have found a separate pathway to maintain telomere length termed ALT (Alternative Lengthening of Telomeres). The exact mechanism behind telomere maintenance in the ALT pathway has not been elucidated, but likely involves multiple recombination events at the telomere.
E.V. Gostjeva et al (MIT) recently imaged colon cancer stem cells and compared them to fetal colon stem cells trying to make a new colon; they were the same.
Dr. Elizabeth Blackburn, University of California, San Francisco (UCSF), et al has shown work that reveals that mothers caring for their very sick children have shorter telomeres when they report that their emotional stress is at the greatest point. She also found telomerase active at the site of blockages in coronary artery tissue. This could be why heart attacks can come on so suddenly: Telomerase is driving the growth of the blockage.
Other work has shown that the poor of society have shorter telomeres than the rich. Short telomeres can lead to telomeric crisis and the initiation of cancer if many other conditions are also met, or so the discussion goes at this point.
Dr. Blackburn and the two other co-discoverers of telomerase won the Lasker Prize (2006) for the discovery of telomerase and subsequent work on telomerase. Dr. Blackburn also won the 2006 Gruber Genetics Prize for same. Seventy winners of the Lasker have gone on to be awarded the Nobel.
Cri du chat Syndrome (CdCS) is a complex disorder involving the loss of the distal portion of the short arm of chromosome 5. TERT is located in the deleted region, and loss of one copy of TERT has been suggested as a cause or contributing factor of this disease.
Dyskeratosis congenita (DC) is a disease of the bone marrow that can be caused by a mutation in the telomerase RNA subunit, TERC. Mutation of TERC accounts for only 5% of all cases, and, when DC occurs by this mutation, it is inherited as an autosomal dominant disorder. Mutations in the gene Dyskerin (DKC1) account for about 35% of DC cases, and, in this case, the inheritance pattern is X-linked-recessive.
Patients with DC have severe bone marrow failure manifesting as abnormal skin pigmentation, leucoplakia (a white thickening of the oral mucosa), and nail dystophy, as well as a variety of other symptoms. Individuals with either TERC or DKC1 mutations have shorter telomeres and defective telomerase activity in vitro than other individuals of the same age.
There has also been one family in which autosomal dominant DC has been linked to a heterozygous mutation in TERT. These patients also exhibited an increased rate of telomere-shortening, and genetic anticipation (i.e., the DC phenotype worsened with each generation).