ZOOHCC - 501: Molecular Biology (Theory)
Unit 2: DNA Replication
Telomeres
Aging
Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must "cap" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or "uncapped" telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many "uncapped" telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.
Structure
Telomeres are present at the ends of all eukaryotic chromosomes. It consists of a short nucleotide sequence that is repeated several times. They do not code for any proteins.
The order in which they are repeated depends on the species. The number of copies of the repeat unit varies from chromosome to chromosome or even within the same chromosome in different cells. A normal human cell has about 500 to 3000 repetitions, which gradually become shorter. In some cells, such as germline cells and cancer cells, telomeres do not shorten with age.
The basic repeating unit pattern for most species is 5`-T1-4A0-1G1-8-3`. Telomeres usually end with a guanine-rich single strand at the 3' end. In humans, a T-loop is formed at the end of his 3′ single strand. The protein shelterin protects telomeres from deterioration and alteration.
The human repeat is 5'-TTAGGG-3'. In the plant Arabidopsis thaliana it is TTTAGGG. Additional sequences related to telomeres are found in most species.
Telomeres containing tandem repeats of TTAGGG are very common in vertebrates. It is found in over 100 species, including birds, reptiles, amphibians, fish and mammals.
In most prokaryotes, the DNA is circular, so telomeres are not found. Telomeres are found in some prokaryotes with linear DNA, but their structure differs from eukaryotic cells. They are in the form of hairpin loops, formed from single strands or attached to proteins.
Function
Telomeres arise from imperfect replication at the ends of chromosomes. With each replication cycle, a piece of DNA is lost. These protective end caps ensure that genetic information is preserved and not lost in the process. They play an important role in aging. They are essential for attracting the telomerase replication machinery to the ends of chromosomes and regulating its function there. In addition, telomeres are required to stabilize eukaryotic chromosomes in a variety of ways. Telomeres protect chromosome ends from recognition by the cell's DNA damage response system. It seals the ends of chromosomes to prevent degradation and fusion. The fused chromosome may have segregated incorrectly in meiosis or mitosis. Telomeres are often located beneath the nuclear membrane, and their unique association with the spindle pole body of fission yeast is essential for normal conduction of meiotic recombination.
Role in aging and cancer
Telomeres play an important role in cellular aging. Telomeres shorten with each replication, and when they become too short, cells stop replicating, leading to senescence and apoptosis. Therefore, it acts as a biological clock for cellular aging. It also causes oncogenic transformation of cells.
The rate of telomere shortening can be reduced with a better lifestyle, diet, and activity. It delays the onset of age-related diseases and prolongs life.
A special enzyme called "telomerase" can extend the length of telomeres. It exists in infinitely dividing cells. Unicellular eukaryotes, egg and sperm cells, blood cells and even cancer cells.
Scientists have observed that in cancer cells, telomeres are too short, and when they reach a critical point, telomerase is reactivated, causing cancer cells to grow out of control. Most cancer cells such as breast cancer, prostate cancer, lung cancer, pancreatic cancer Contains telomerase, which maintains telomere length and prevents apoptosis. Research into anticancer drugs that target telomerase is underway.
