Telomeres are the structure of nucleoproteins that are present at the end of chromosomes in eukaryotes (Rhodes & Giraldo, 1995). These telomeres are similar to the cap that preserves the strength of linear DNA in cell replication (Lee & Pellegrini, 2022).
Telomere was first discovered in the rDNA mini chromosome ends of Tetrahymena that contains 20-70 hexametric repeats of the sequence ‘TTGGGG’ after the identification of chromosome ends that are protected against re-arrangement events in intra-chromosomal breaks in the year 1930. Telomeres have repeated sequences that are bound by multiple telomeric interacting proteins.
A recent search has revealed that most eukaryotic telomeres are characterized by tandem repeats of short GT-rich sequences consisting of 6-8 base pair sequences, which may be repeated over hundreds to thousands of times and may vary in number and length according to the species (Lu et al., 2013; Verma et al., 2022).
Structure of Telomeres
Most eukaryotes have repetitive DNA at the end of the chromosome, mainly composed of sub-telomeric and telomeric sequences (Giardini et al., 2014). The telomere structure has repeated non-coding nitrogenous bases (5’-TTAGGG-3’). In humans, the telomeric segments consist of 5,000-15,000 base pairs (Lee & Pellegrini, 2022). The end of each chromosome has a G-rich strand running from 5’ to 3’ towards the terminus, extending 12-16 nucleotides in complementary C-rich strands. The G-rich strand of telomere helps in DNA sequencing, which is synthesized by an RNA template (Blackburn, 1991).
Functions of Telomere
The primary function of the telomere is chromosomal stability and preventing degradation. They also help in damage response and prevent accidental recombination (Lee & Pellegrini, 2022). Telomeres play a crucial role in malignant transformation and cancer development, as they can shorten cell proliferation and suppress tumor cells for further formation (Dong et al., 2005). Telomerase-associated components can influence cell type and stages of cell division (Harrington, 2003), helping to protect against inter-chromosomal fusion and recombination. Furthermore, it conserves the genomic information (Verma et al., 2022).
Role of Telomeres in Solving the End Replication Problem
The replication of telomeres is a complex phenomenon. It has a multistep relying on dynamic interactions. Telomeres contain the enzyme telomerase and various telomeric proteins that maintain cell genome integrity. This was observed from the late 1930s to the 1980s (Giardini et al., 2014).
During cell division, DNA replication faces difficulty copying the ends of each chromosome due to unconventional replication of enzymes. As a result, the “end replication problem” arises. This leads to telomere shortening in each cell division. To solve this problem, enzyme telomerase extends telomeres by adding specific DNA sequences to their ends, helping them to increase the cellular lifespan and maintain chromosomal stability (Bonnell et al., 2021)
Telomerase Shortening and Cellular Aging
The cells of mammals have repeated hexanucleotide motifs that consist of TTAGG, protecting the chromosomes from degradation and addition. The telomere length demonstrates replicative capacity in human fibroblast and correlates between dicentric chromosome and senescent telomeric length. During cell division, the length of telomeres shortens in somatic (non-reproductive) human cells and after reaching a disparagingly short length may lead to senescence. Additionally, their morphological characters are also changed (Mathieu et al., 2004).
Cellular Aging- Aging is the process through which physiological functions gradually decline, leading to cell death. The factors contributing to cellular aging include damage to telomeres and DNA, mitochondria dysfunction, and epigenetics dysregulation. These factors lead to various diseases like cancer, cardiovascular disease, diabetes, neurodegenerative disorders, chronic obstructive pulmonary disease, chronic kidney disease, osteoporosis, sarcopenia, and even stroke (Lulkiewicz et al., 2020).
Telomerase: The Telomere-Maintaining Enzyme
Telomerase is an enzyme responsible for adding DNA to chromosomes that helps to maintain the length of chromosomes. It is also a reverse transcriptase ribonucleoprotein composed of a telomerase reverse transcriptase (TERT) protein and a noncoding RNA component (TER, telomerase RNA) (Giardini et al., 2014). In eukaryotes, telomerase, a telomeric enzyme includes a catalytic protein subunit known as telomerase reverse transcriptase (hTERT) and a core RNA component (hTR) that synthesizes and maintains the telomere structure with uncontrolled cell growth and is linked to the development of cancer. By inhibiting telomerase in cancer cells, certain therapies can potentially limit the growth of tumors, making it possible for cancer treatment (Ghareghomi et al., 2021).
Telomerase and Disease
The production of reactive oxygen species (ROS) in telomeres induces cellular aging, especially when influenced by numerous stressors such as mitochondrial dysfunction, unhealthy lifestyle choices, and medical treatments like chemotherapy and radiation. In obese people, experiencing psychological stress, the G-rich telomeres have less potential for DNA repair and, are more susceptible to oxidative stress, leading to shorter telomeres whereas, longer telomeres are associated with higher physical activity (Lee & Pellegrini, 2022).
Gene amplification or promoter methylation may result in the deregulation of hTERT expression and as a result, approximately 90% of tumor cells produce telomerase. The upregulation of telomerase in several cancers associated with hTERT makes it a focal target for cancer immunotherapy. Some techniques such as oligonucleotide inhibitors, immunotherapy, and gene therapy induce telomere shortening, activate T-lymphocytes against telomerase, and selectively destroy tumor cells, respectively (Lee & Pellegrini, 2022).
Studies have also found that the longer telomeres in leukocytes are associated with more years without diseases. When the cells are measured from the bloodstream, telomeres differ genetically and are influenced by factor such as stress, pollution, and lifestyle choices. These factors reflect cellular health and indicate potential disease risks and overall health profile (Lulkiewicz et al., 2020).
Factors Affecting Telomere Length
Telomere length varies between individual chromosomes, they do not have the same telomere length in all individuals. This can affect the measurement of telomeres. While several methods exist to measure telomere length, they are more suitable for general screening purposes than providing highly precise or detailed results. These methods may lack detailed or specific analyses. Environmental stimuli such as hormonal profile fluctuations or therapeutic interventions alter telomere length (Lulkiewicz et al., 2020).
Ethical and Future Considerations
Extensive research and understanding of the complex mechanism of the chromosomal instability resulting from telomere maintenance are crucial for addressing the weakness of anti-telomerase therapies and the development of new drugs. Identifying associated biomarkers can enable the classification of tumors with their appropriate treatment plans (Mathieu et al., 2004).
Conclusion
Telomeres are the structures that play an essential role in chromosome stability, cellular aging, and overall disease risk. They also play a crucial role in preventing chromosomal degradation. Their presence supports the endurance of cellular information and they also help in cancer therapy. Telomerase, an enzyme can be affected by various factors such as environmental stress and cellular damage. Understanding these influences may lead to improvements in overall health. Telomeres play a vital role in genomic stability in eukaryotes and in preserving cellular information. Therefore, telomere biology contributes to the strategy of healthy aging. Future research should focus on improving anti-telomerase therapies by understanding telomere-related chromosomal instability and developing more effective treatments.
References
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