Telomeres are distinctive cap-like structures present at the end of each strand of DNA. The name “Telomere” comes from the ancient Greek language; télos means ‘end’, and méros means ‘part’, so the literal meaning of telomere “ending part”. These are regions of repetitive nucleotide sequences that protect the DNA from damage. Almost all eukaryotes possess telomeres. The telomeres protect the terminal ends of chromosomes from degradation and ensure the integrity of DNA.
In this article, we will discuss the structure and function of telomeres and their associated proteins. We will have a closer look at the impact of different lifestyle factors and environmental factors on the length of telomeres. Moreover, our discussion will focus on the role of a special enzyme associated with telomeres called the telomerase enzyme. Lastly, we will have a brief account of the research about telomerase lengthening.
Structure & Function of Telomeres
Telomeres do not contain genes but are comprised of repeat sequences. These are bound by multiple interacting proteins associated with telomeres. In a mature mammalian cell, the DNA of the telomere contains the double-stranded repeated sequence of TTAGGG. This sequence is followed by terminal 3′ G-rich single-stranded overhangs. The single-stranded telomere G overhangs form G-quadruplexes.
The G-quadruplexes play an important role in the protection of telomere, suppression of recombination, and inhibition of telomere extension. According to another research, G-quadruplexes are poor substrates for telomerase (an enzyme which we will discuss later in the article). In a telomere, the long single-stranded DNA curls around to make a circle. Many proteins associated with telomeres stabilize this circle. This results in a large loop structure which is known as T-loop.
The length of telomeres varies greatly between different organisms. Research shows that in yeast, there are almost 300 base pairs that make the length of the telomere. On the other side, in humans, there are many thousand base pairs are present in telomeres. These arrays are present in the form of six to eight base pairs that are repeated again and again.
Telomers play important role in two protective functions. First, the proteins associated with telomeres prevent the activation of the cell’s system for monitoring DNA damage. Second, the telomeric DNA provides protection against shortening of the genes in the same way a plastic cover at the end of shoelaces does. A point should be kept in mind that the telomeres just postpone instead of completely preventing the erosion of genes.
- The End replication problem
The process of DNA synthesis is unidirectional which means that the synthesis progresses 5’-3’ and the DNA polymerase does not replicate the sequences present at the 3’-ends. Moreover, a primer is also required to initiate the process of replication. In replication, there are two strands; the leading strand which is oriented 5’-3’, and the lagging strand which is oriented 3’-5’.
On the leading strand, the DNA-polymerase enzyme replicates the DNA from the starting point all the way to the end of the leading strand. In the process, the primer that is made of ribonucleic acid is excised and substituted with DNA. This does not happen in the case of the lagging strand because it is oriented 3’-5’ with respect to the replication fork. This scenario requires repeated synthesis of primers further 5′ of the sites of initiation. In this way, the last primer sits near the 3′-end of the template.
Initially, it was thought that the last primer would sit at the very end of the template. When it is removed the DNA polymerase enzyme would be unable to make the so-called ‘replacement DNA’ from the 5’-end of the strand. In this case, the template nucleotides that were previously paired to the last primer would not be replicated. This has made the scientists question that whether the last primer sits exactly at the 3’-end of the template. It was demonstrated that its synthesis takes place at a distance of 70-100 nucleotides.
There is a risk of losing potentially vital genetic code in this process due to possible degradation of the coding sequence. The telomeres play an important role here. They “cap” these sequences and act as a buffer for these coding sequences and are progressively degraded in the complex process of DNA replication.
The telomeric DNA becomes shorter in the dividing somatic cells of older people. That is why they are thought to be related to the aging process of the individual. But here is a problem, If the same process happens in the germ cells, and the chromosomes become shorter and shorter, some important genes would be missing from the gametes. Actually, this does not happen this way. Instead, an enzyme called telomerase enzyme restores the original length in eukaryotic germ cells and prevents this from occurring. We will discuss more about the telomerase enzyme later in this article.
- Role in Cell Cycle
Telomeres play a vital role in the regulation of the cell cycle. According to research, the shortening of telomeres may prevent or block cell division. This is a very important feature because limiting the number of cell divisions may prevent cancer and genomic instability. However, in some other cases, the telomeres may be involved in increasing the susceptibility to cancer. This happens because shortened telomeres impair immune function. Moreover, if the telomeres become too short, there is a great chance of unfolding of their closed structure.
If the unfolding happens, the cell may detect this unfolding as DNA damage. Upon these signals, the cell may stop its growth, or enter senescence. The cell may also begin apoptosis (programmed death of the cell). That is why shortened telomeres are thought to be involved in many age-related diseases because organs deteriorate when most of their cells undergo apoptosis.
Telomerase is a ribonucleoprotein that adds repetitive nucleotide sequences to the ends of DNA. Telomerase is a reverse transcriptase enzyme that is active in gametes. In somatic cells, telomerase is present in very low numbers. Most eukaryotes possess telomerase but interestingly, the fruit fly Drosophila melanogaster lacks this enzyme. Research has shown that fruit fly uses retrotransposons to maintain the telomeres. The human telomerase complex consists of two molecules each of TERT (telomerase reverse transcriptase), Telomerase RNA, and DKC1 (dyskerin). The telomerase reverse transcriptase uses double-stranded RNA to make single-stranded DNA.
Telomerase restores the telomere “cap” and thus prevents the telomeres from shortening during mitosis. In the absence of telomerase, when a cell divides, again and again, it reaches its Hayflick limit. At the Hayflick limit (between 50-70 cell divisions), the process of cell division stops. But in those cells where telomerase enzyme is present, it allows the cell to divide again and again without ever reaching the Hayflick limit by replacing small bits of lost DNA. Telomerase is highly expressed in embryonic stem cells, sperm cells, and activated T and B cells.
- Clinical implications
Having discussed the function of telomerase, let us move towards its clinical importance.
Telomerase acts as a biomarker for the detection of cancer in the body because research has shown that most cancer types express high levels of telomerase. Actually, telomerase activity is necessary for the preservation of cancer cells. That is why inhibition of telomerase can produce good results in the suppression of many cancer types. However, it is not possible to destroy large tumors by only inhibiting telomerase. In the case of large tumors, surgery, radiation, and chemotherapy combined with telomerase inhibition may provide great results.
The identification of telomerase activity is done by the expression of hTERT (telomerase reverse transcriptase). The expression of hTERT may also distinguish between malignant and benign tumors because malignant tumors show higher hTERT expression.
Scientists have developed two telomerase vaccines. One vaccine makes cytotoxic T cells to kill the telomerase-active cells. The other is a peptide that is recognized by the defense system of the body and leads to the killing of telomerase-active cells. Scientists have conducted initial testing of vaccines in mouse models and now they have also started clinical trials.
Mutations in telomerase reverse transcriptase (TERT) may give rise to some rare human disease. For example, these mutations may predispose a person to aplastic anemia (bone marrow failure). Moreover, the loss of one copy of TERT may play the role of contributing factor in the development of Cri du chat syndrome. In Dyskeratosis congenita (DC), mutations in telomerase subunits (TERT, TERC, DKC1) leads to abnormal skin pigmentation, leukoplakia, and nail dystrophy.
Telomere shortening may indicate the pace of aging and it may also predict the life span. In this part, we will discuss the relation of telomere shortening with oxidative damage, age, and cancer.
- Oxidative damage
Oxidative stress damages the DNA and shortens the telomeres. The cause of the high destruction rate in telomers due to oxidative stress is still a matter of research. Some researchers believe that it is due to the low activity of DNA repair systems in these regions. Some studies suggest that there is a relation between an antioxidant diet and telomere length. Another research has shown that there is a moderate increase in the risk of breast cancer among women having shorter telomeres and eating a diet low in vitamin C, vitamin E, and beta carotene. This suggests that DNA damage due to oxidative stress may interact with telomere shortening to increase the risk of breast cancer.
- Association with aging
It is a well-known fact that telomere length decreases with age. This is a normal cellular process. Studies have shown that telomere length in humans decreases at a rate of 25–28 base pairs per year. When the telomere length in a person becomes shorter than the average telomere length for a specific age group or a specific population, the risk of age-related diseases and/or decreased lifespan in that person increases. This happens because when telomere length reaches below a critical limit, cell division stops, and the cells undergo senescence or apoptosis.
Telomere length of an individual is affected by a variety of factors including genetic, epigenetic make-up, exercise, body weight, environment, social and economic status, and smoking. However, gender is not significantly related to the rate of telomere loss in an individual. According to some studies, lifestyle factors such as obesity, lack of exercise, smoking, and consumption of a highly processed diet can increase the rate of telomere loss. It eventually leads to an increased pace of aging and may even result in premature death.
Accelerated telomere shortening due to various factors described earlier, leads to the early onset of many age-related health diseases. These diseases include coronary heart disease, myocardial infarction, heart failure, diabetes mellitus, cancer, and osteoporosis. Abnormal and excessive telomere shortening can greatly affect health and lifespan. The risk of myocardial infarction is significantly increased in those individuals who have shorter leukocyte telomeres. Moreover, several studies have shown that people with shorter telomeres have a much higher rate of mortality than those with longer telomeres.
In some cases, individuals may be born with shorter telomeres due to some genetic disorder. In these individuals, there is a great risk of the development of premature aging, premature heart disease, and premature death. For example, deficiency of telomerase RNA gene can lead to shorter telomeres resulting in Dyskeratosis congenita that is associated with progressive bone marrow failure, skin pigmentation, increased risk of cancer, increased susceptibility to infections, and premature death in adults.
- Association with cancer
Extremely short telomeres may also induce genomic instability. This happens because short telomers mediate interchromosomal fusion. This process leads to the development of cancer due to telomere stabilization. The activity of the telomerase enzyme in most cancer cells is very high whereas telomere length is shorter. Individuals with shorter telomeres are at a greater risk for the development of various cancers such as lung cancer, gastrointestinal cancer, and head and neck cancers. The good news is that inhibition of telomere maintenance mechanisms and continued telomere shortening can be used in the destruction of cancer cells.
Impact of lifestyle and environmental factors
Several factors affect the telomere length and the process of aging. These factors may be related to lifestyle such as smoking, exercise, and eating habits or they may be related to other factors such as social and psychological factors. In this part, we will briefly discuss some of these factors.
You know that “Smoking is injurious to health”, and one of the ways smoking destroys health is that it accelerates the process of telomere shortening. Studies have shown that when the dosage of cigarette smoking is increased, the rate of telomere shortening increases. Smoking increases oxidative stress and increases the pace of aging. A research states an interesting piece of information that the telomere shortening by smoking 1 pack of cigarettes daily for 40 years is equal to the telomere shortening in 7.4 years.
Obesity increases oxidative stress that causes DNA damage and telomere shortening. According to a research, increased BMI and increased waist circumference is significantly related to elevated levels of reactive oxygen species. The mechanism of oxidative stress due to obesity may be deregulated production of adipocytokines. A research has shown that lack of antioxidant defense and in obese animals is the reason for increased oxidative stress.
Loss of telomeres in some obese patients has been calculated to be equivalent to 8.8 years of life. This is even worse than the damage caused by smoking continuously for 40 years. Moreover, in the women of the same age group, obese women are found to have shorter telomeres.
Exposure to environmental pollution, elevated levels of toluene and benzene in the air, and increased polycyclic hydrocarbons in the environment are associated with increased telomere shortening. Studies have shown that office workers and traffic wardens have shorter telomeres in a specific age group.
Another study has found that there is an increased risk of lung cancer in cake-oven workers. Telomere shortening in lymphocytes of cake-oven workers is also associated with hypomethylation of p53 promotors, which results in the expression of p53 that leads to apoptosis. That is why increased exposure to harmful and toxic agents causes DNA damage and increases cancer risk.
Psychological stress induces the release of glucocorticoid hormones which reduce the levels of antioxidant proteins. In this way increased stress results in increased oxidative damage to DNA. This process eventually leads to accelerated telomere shortening. Studies have shown that those women who are exposed to greater stress in their daily life have reduced telomerase activity and shorter telomeres. The telomere shortening in these women was calculated to be equivalent to 10 years of life. This shows that women under stress are more prone to age-related health problems such as coronary heart disease, high blood pressure, and heart failure.
Our dietary habits have an important relationship with the length of telomeres. Increased intake of fiber decreases waist circumference and it is related positively to telomere length. A research conducted on rats has shown that by decreasing the protein content of food, the lifespan of rats can be increased. A protein-restricted diet in rats has shown reduced growth, increased lifespan, longer telomeres, and suppression of appetite. Some researchers believe that increased life expectancy in some countries of the world (such as Japan) is also due to reduced protein levels and increased carbohydrate levels in their diet.
Omega-3 fatty acids contain antioxidants that produce beneficial effects in the body. These fatty acids decrease the oxidative damage to DNA and thus slow down the process of telomere shortening and aging. Moreover, consumption of a diet rich in antioxidants such as beta carotene and vitamin C lowers the risk of age-related health problems. Individuals who consume an antioxidant-rich diet have longer telomeres.
Exercise reduces harmful fat, helps in the elimination of waste products, and reduces oxidative stress. Increasing the duration of exercise leads to reduced oxidative stress and reduced DNA damage. Reduction in both oxidative stress and DNA damage leads to the preservation of telomeres. According to research, increased exercise is associated with increased telomerase activity. Moreover, exercise may cause suppression of several apoptosis proteins such as p53 in experimental animals. Athletes show elevated telomerase activity and reduced telomere shortening in the chromosomes of their leukocytes. However, nonathletes show shorter telomeres and increased oxidative stress.
- Telomeres are the distinctive cap-like structure present at the end of each strand of DNA and provide protection against DNA damage. They are comprised of repeated nucleotide sequences, but they do not contain any gene. Telomeres play role in two important protective functions. The first is preventing the activation of the cell’s system of monitoring DNA damage and the second is the protection of DNA against the shortening of genes. In the replication of DNA of somatic cells, some part of the telomere is lost and with continuous cell division, the telomere becomes shorter and shorter. In gametes, an enzyme called telomerase restores the length of the telomeres and the cells keep on dividing forever.
- Telomerase complex consists of TERT (telomerase reverse transcriptase), Telomerase RNA, and DKC1 (dyskerin) and it is highly active in sperm cells and cancer cells. Telomerase can also be used as a biomarker for many cancers as most of the cancer cells show high telomerase activity. Mutations in telomerase reverse transcriptase may give rise to rare human diseases such as Dyskeratosis congenita. Telomere shortening is the result of aging, oxidative damage, and other factors. Reactive oxidative species cause damage to DNA which leads to the shortening of telomeres.
- The rate of telomere shortening may predict lifespan because increased telomere shortening is positively related to an increased pace of aging. There are various lifestyle and environmental factors that are related to the length of telomeres. Smoking and obesity increase oxidative stress that leads to the shortening of telomeres. That is why obese people are at a greater risk of developing age-related health problems. Moreover, environmental pollution and stress can negatively affect the length of telomeres. Consuming a diet rich in antioxidants, relieving stress through meditation techniques, and increasing the duration of exercise effectively lowers oxidative damage and leads to increased health and increased life expectancy.
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