Telomeres are nucleoprotein structures located at the ends of chromosomes in eukaryotes (Rhodes & Giraldo, 1995).
Telomeres function like a protective cap that maintains the integrity of linear DNA during cell replication (Lee & Pellegrini, 2022).
Telomeres were first discovered at the ends of rDNA mini-chromosomes in Tetrahymena, where they contained 20–70 hexameric repeats of the sequence ‘TTGGGG’, following the identification of chromosome ends that are protected against intra-chromosomal break rearrangement events in the 1930s.
Telomeres consist of repeated sequences that are bound by multiple telomeric-interacting proteins.
Recent research has shown 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 hundreds to thousands of times and may vary in number and length depending on the species (Lu et al., 2013; Verma et al., 2022).
Structure of Telomeres
Most eukaryotes possess repetitive DNA at the ends of their chromosomes, mainly consisting of sub-telomeric and telomeric sequences (Giardini et al., 2014).
The structure of telomeres includes repeated non-coding nitrogenous base sequences, specifically (5’-TTAGGG-3’).
In humans, telomeric segments are composed of 5,000–15,000 base pairs (Lee & Pellegrini, 2022).
Each chromosome end features a G-rich strand running from 5’ to 3’ towards the terminus, extending 12–16 nucleotides in the complementary C-rich strands.
The G-rich strand of the telomere aids in DNA sequencing and is synthesized using an RNA template (Blackburn, 1991).
Functions of Telomere
The primary function of the telomere is to ensure chromosomal stability and prevent degradation.
Telomeres help in the damage response and prevent accidental recombination (Lee & Pellegrini, 2022).
Telomeres play a crucial role in malignant transformation and cancer development by shortening cell proliferation and suppressing tumor cells from further formation (Dong et al., 2005).
Telomerase-associated components can influence the cell type and stages of cell division (Harrington, 2003).
Telomeres help protect against inter-chromosomal fusion and recombination.
Telomeres conserve genomic information (Verma et al., 2022).
Role of Telomeres in Solving the End Replication Problem
The replication of telomeres is a complex phenomenon involving multiple steps and dynamic interactions.
Telomeres contain the enzyme telomerase and various telomeric proteins that help maintain cell genome integrity, a discovery observed from the late 1930s to the 1980s (Giardini et al., 2014).
During cell division, DNA replication encounters difficulty copying the very ends of chromosomes due to the unconventional action of replication enzymes.
This difficulty results in the "end replication problem," leading to telomere shortening with each cell division.
To solve this problem, the enzyme telomerase extends telomeres by adding specific DNA sequences to their ends.
This extension helps increase the cellular lifespan and maintain chromosomal stability (Bonnell et al., 2021).
Telomerase Shortening and Cellular Aging
Mammalian cells have repeated hexanucleotide motifs consisting of TTAGG, which protect chromosomes from degradation and addition.
Telomere length demonstrates the replicative capacity in human fibroblasts and shows a correlation between dicentric chromosomes and senescent telomeric length.
During cell division, telomere length shortens in somatic (non-reproductive) human cells.
After reaching a critically short length, telomere shortening can lead to cellular senescence.
Additionally, the morphological characteristics of the cells also change (Mathieu et al., 2004).
Telomere Shortening
Aging is the process through which physiological functions gradually decline, leading to cell death.
Factors contributing to cellular aging include damage to telomeres and DNA, mitochondrial dysfunction, and epigenetic dysregulation.
These factors lead to various diseases like cancer, cardiovascular disease, diabetes, neurodegenerative disorders, chronic obstructive pulmonary disease, chronic kidney disease, osteoporosis, sarcopenia, and stroke (Lulkiewicz et al., 2020).
Telomerase: The Telomere-Maintaining Enzyme
Telomerase is an enzyme responsible for adding DNA to chromosomes, helping to maintain the length of chromosomes.
It is 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 includes a catalytic protein subunit known as telomerase reverse transcriptase (hTERT) and a core RNA component (hTR) that synthesizes and maintains the telomere structure.
Telomerase is associated 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 cancer treatment possible (Ghareghomi et al., 2021).
Telomerase and Disease
The production of reactive oxygen species (ROS) in telomeres induces cellular aging.
Cellular aging is especially influenced by stressors such as mitochondrial dysfunction, unhealthy lifestyle choices, and medical treatments like chemotherapy and radiation.
In obese individuals experiencing psychological stress, the G-rich telomeres have reduced potential for DNA repair and are more susceptible to oxidative stress.
Oxidative stress leads to shorter telomeres.
Longer telomeres are associated with higher levels of physical activity (Lee & Pellegrini, 2022).
Telomere in Healthy and Cancer Cells
Gene amplification or promoter methylation may result in the deregulation of hTERT expression.
Approximately 90% of tumor cells produce telomerase as a result of hTERT deregulation.
The upregulation of telomerase in several cancers associated with hTERT makes it a focal target for cancer immunotherapy.
Techniques such as oligonucleotide inhibitors, immunotherapy, and gene therapy are used to induce telomere shortening, activate T-lymphocytes against telomerase, and selectively destroy tumor cells, respectively (Lee & Pellegrini, 2022).
Studies have found that longer telomeres in leukocytes are associated with more years without diseases.
When measured from the bloodstream, telomeres differ genetically and are influenced by factors such as stress, pollution, and lifestyle choices.
These factors reflect cellular health and indicate potential disease risks and the overall health profile (Lulkiewicz et al., 2020).
Factors Affecting Telomere Length
Telomere length varies between individual chromosomes, and they do not have the same length in all individuals.
This variation can affect the measurement of telomeres.
While several methods exist to measure telomere length, they are more suitable for general screening purposes than for providing highly precise or detailed results.
These methods may lack detailed or specific analyses.
Environmental stimuli, such as hormonal profile fluctuations or therapeutic interventions, can alter telomere length (Lulkiewicz et al., 2020).
Ethical and Future Considerations
Extensive research and understanding of the complex mechanisms of chromosomal instability resulting from telomere maintenance are crucial.
This research is essential for addressing the weaknesses of anti-telomerase therapies and for the development of new drugs.
Identifying associated biomarkers can enable the classification of tumors and their appropriate treatment plans (Mathieu et al., 2004).
Conclusion
Telomeres are essential structures that play a crucial role in chromosome stability, cellular aging, and overall disease risk.
They help prevent chromosomal degradation and support the endurance of cellular information.
Telomeres also play a significant role 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 are vital for genomic stability in eukaryotes and for preserving cellular information.
Therefore, telomere biology contributes to strategies for healthy aging.
Future research should focus on improving anti-telomerase therapies by understanding telomere-related chromosomal instability and developing more effective treatments.
References
Bonnell, E., Pasquier, E., & Wellinger, R. J. (2021). Telomere replication: Solving multiple end replication problems. Frontiers in Cell and Developmental Biology, 9, 668171.
Blackburn, E. H. (1991). Structure and function of telomeres. Nature, 350(6319), 569-573.
Dong, C. K., Masutomi, K., & Hahn, W. C. (2005). Telomerase: Regulation, function, and transformation. Critical Reviews in Oncology/Hematology, 54(2), 85–93.
Ghareghomi, S., Ahmadian, S., Zarghami, N., & Kahroba, H. (2021). Fundamental insights into the interaction between telomerase/TERT and intracellular signaling pathways. Biochimie, 181, 12–24.
Giardini, M. A., Segatto, M., Da Silva, M. S., Nunes, V. S., & Cano, M. I. N. (2014). Telomere and telomerase biology. Progress in Molecular Biology and Translational Science, 125, 1–40.
Harrington, L. (2003). Biochemical aspects of telomerase function. Cancer Letters, 194(2), 139-154.
Lee, J. & Pellegrini, M. V. (2022). Biochemistry, telomere, and telomerase. StatPearls [Internet], StatPearls Publishing. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK576429/?report=classic
Lu, W., Zhang, Y., Liu, D., Songyang, Z., & Wan, M. (2013). Telomeres: Structure, function, and regulation. Experimental Cell Research, 319(2), 133–141.
Lulkiewicz, M., Bajsert, J., Kopczynski, P., Barczak, W., & Rubis, B. (2020). Telomere length: How the length makes a difference. Molecular Biology Reports, 47(9), 7181–7188.
Mathieu, N., Pirzio, L., Freulet-Marrière, M. A., Desmaze, C., & Sabatier, L. (2004). Telomeres and chromosomal instability. Cellular and Molecular Life Sciences, 61(6), 641–656.
Rhodes, D., & Giraldo, R. (1995). Telomere structure and function. Current Opinion in Structural Biology, 5(3), 311-322.
Verma, A. K., Singh, P., Al-Saeed, F. A., Ahmed, A. E., Kumar, S., Kumar, A., Dev, K., & Dohare, R. (2022). Unravelling the role of telomere shortening with aging and their potential association with diabetes, cancer, and related lifestyle factors. Tissue and Cell, 79, 101925.
