Telomeres
Introduction
The idea of telomeres emerged during the 1930s when Creighton and McClintock (1931), and Müller (1938) observed a distinct structure at the tips of chromosomes in Zea mays (corn plant) and Drosophila melanogaster (fruit fly). They proposed that this structure played a crucial role in preventing the fusion of chromosome ends. Müller introduced the term "telomere," derived from the Greek words telos, signifying "end," and meros, signifying "part," hence translating to "end part”. In fact, composed of repetitive nucleotide sequences forming a protective "cap structure," telomeres are protein formations located at the ends of each eukaryotic deoxyribonucleic acid (DNA) chromosome arm, serving to maintain chromosome integrity and prevent chromosomal degradation (Chakravarti et al., 2021; Lee & Pellegrini, 2022).
Telomeres are crucial structures for maintaining the structural integrity of linear DNA throughout each replication cycle. The main role of telomeres encompasses shielding DNA ends from self-binding or interconnection with other chromosomal ends, thereby enabling complete chromosomal replication (Lee & Pellegrini, 2022). Furthermore, as part of normal cellular processes, a fraction of telomeric DNA is naturally lost with each cell division. When telomeres reach a critical length, they are recognized as DNA double-stranded breaks, prompting replicative senescence, a state where cells cannot divide further, and/or apoptosis, programmed cell death. Consequently, telomere length acts as a biological clock, regulating the lifespan of both the cells and the organism (Shammas, 2011; Srinivas et al., 2020). Telomeres also serve to shield the chromosome's free ends from resembling DNA double-stranded breaks, thereby protecting them from unwanted DNA repair. Pathologically, when the telomere synthesis mechanism is dysregulated, it can result in cellular immortality, potentially triggering oncogenesis and tumorigenesis. Additionally, telomeres are closely associated with significant contributions to human ageing (Lee & Pellegrini, 2022).
Structure of Telomeres
The first telomeres to be characterised were from the ciliated protozoa Tetrahymena thermophila. Telomeres consist of 20–70 tandem repeat sequences of non-coding nitrogenous bases (5'-TTAGGG-3'), typically spanning between 10 to 15 kilobases. They encompass both proximal double-stranded and distal single-stranded regions, with subtelomeres and interstitial sections separating the repeats from the rest of the chromosome. At the 3′ end, they culminate in a single-stranded 75- to 300-nucleotide overhang rich in guanine nucleotides, known as the G-tail. The conservation of this identical sequence has been noted across more than 90 eukaryotic species, spanning all mammals. This suggests that this nuclear sequence has remained remarkably consistent throughout evolutionary history (Chakravarti et al., 2021; Jafri et al., 2016; Lee & Pellegrini, 2022; Shammas, 2011; Shay, 2019; Srinivas et al., 2020).
The 3′ G-rich overhang plays a crucial role in facilitating the formation of a higher-order structure resembling a "lasso" in telomeric DNA. In this structure, the 3′ single-stranded overhang folds back and infiltrates into the homologous double-stranded TTAGGG region, creating what is known as a telomeric loop (T-loop).
Figure 1
Depiction of the formation of the T-loop by the 3’ overhang.
Created using BioRender.com
This T-loop serves to protect the 3′ end by shielding it from recognition by the DNA damage response (DDR) machinery. It is worth noting that the biochemical structure of the T-loop is thermodynamically unfavourable, thereby requiring the involvement of proteins in both its assembly and maintenance. Additionally, the G-tail can adopt a four-stranded helical structure termed the G-quadruplex.
Figure 2
Depiction of the G - quartet and G- quadruplex, formed by stacking G- quartets
Created using BioRender.com
This structure is formed by overcoming kinetic barriers through intra-molecular folding and the stacking of G-quartets. Each quartet is constituted by the association of four guanine molecules around a monovalent metal ion. These compact and stable structures, apart from serving as a telomeric cap, also impede access to the telomerase, the enzyme responsible for elongating the telomeres (Jafri et al., 2016; Lee & Pellegrini, 2022; Srinivas et al., 2020).
Telomere Associated Proteins
Shelterin complex
Telomere maintenance is a complex process that relies on a vast network of various protein complexes at the telomeres (Lu et al., 2013). Among these complexes, the shelterin complex, also known as the telosome, stands out as a critical protein in protecting telomere integrity and regulating telomere length. Comprising six essential proteins, the shelterin complex allows for vital functions necessary for telomere stability and function (Barral & Déjardin, 2020).
One important aspect of shelterin proteins is their role as telomere-binding proteins, which they accomplish through sequence-specific interactions with telomeric DNA. These proteins have dual functions crucial for telomere maintenance. Firstly, they recruit other proteins necessary for the proper functioning of the DNA damage response mechanism. Secondly, they play an important role in controlling telomere length by facilitating the recruitment of the telomerase (Barral & Déjardin, 2020).
However, the effectiveness of shelterin proteins in protecting telomeres diminishes when telomeres reach critically short lengths. At this stage, shelterin proteins struggle to bind effectively to the telomeres, leading to a decrease in telomere protection and integrity (Barral & Déjardin, 2020).
The shelterin complex is composed of six polypeptides;
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Telomeric repeat- binding factor 1 (TRF-1) - acts as a negative regulator of telomere length, controlling the elongation process (Lu et al., 2013; Fairall et al., 2001).
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Telomeric repeat- binding factor 2 (TRF-2) - serves as a negative regulator of telomere length, but it also plays a crucial role in telomere end protection. TRF2 achieves this by interacting with various factors.
Both TRF1 and TRF2 share a common domain structure, characterised by an N-terminal TRF homology (TRFH) domain. This domain facilitates dimerization and interaction with other telomeric proteins, essential for their function within the telomere complex.
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Repressor/activator protein 1 (RAP1) - does not directly bind to telomeres but instead interacts with the shelterin complex via TRF2, contributing to telomere maintenance and function (Lu et al., 2013).
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TRF interacting nuclear protein 2 (TIN2) - acts as a binding agent within the telosome or shelterin complex, directly interacting with TRF1, TRF2, and the TPP1/POT1 heterodimer (Lu et al., 2013).
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Tripeptidyl peptidase I (TPP1) - directly interacts with TIN2 and POT1, improving their affinity for telomeric single-stranded DNA and facilitating telomerase recruitment to telomeres (Lu et al., 2013).
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Protection of telomeres protein (POT1) - binds to the ‘TTAGGG’ sequence present in telomeric single-stranded DNA and safeguards the 3' end of the single-stranded DNA, contributing to telomere protection. Additionally, POT1 plays a role in regulating telomerase-dependent telomere elongation and interacts with TPP1 at its C-terminus (Lu et al., 2013).
Assembly of the shelterin complex begins by the binding of Telomeric repeat-binding factor 1 (TRF1) and TRF2 to the double stranded TTAGGG sequence present at telomeres. This initial binding event has a cascade of interactions, resulting in the formation of the complete shelterin complex as can be seen in figure 3.
Figure 3
Structure of the shelterin complex. Composed of the six polypeptides mentioned above. Created using Biorender.com
Telomerase
Telomerase, an RNA-dependent DNA polymerase, is primarily responsible for elongating telomeres through the de novo addition of TTAGGG sequences onto 3' chromosome ends. This enzymatic activity effectively reverses the loss of DNA that occurs during each round of replication, providing the molecular foundation for limitless proliferative potential (Cong & Wright, 2002; Lee & Pellegrini, 2022).
The core assembly of telomerase primarily consists of two main elements: a catalytic protein subunit known as telomerase reverse transcriptase (TERT), and a crucial RNA component referred to as human telomerase RNA (hTR). Functioning as a template, hTR carries a sequence that complements one or more telomeric repeats, enabling the synthesis of telomere DNA. Moreover, it participates in the assembly, localization, and catalysis of the telomerase complex (Jafri et al., 2016; Lee & Pellegrini, 2022).
Telomerase-mediated telomere maintenance involves a complex series of molecular steps, including transportation and trafficking of the hTERT protein into the nucleus, assembling hTR and hTERT with accessory components there, and then recruiting them to telomeres during DNA replication at the appropriate time (Jafri et al., 2016). Telomerase activity regulation occurs through numerous mechanisms, including transcriptional regulation, mRNA processing, transportation, and subcellular positioning of each component, and hTR and hTERT maturation, as well as their modifications. During typical human growth and development, telomerase activity is adjusted to meet the specific proliferative requirements of cellular functions, while concurrently upholding proliferative barriers, such as senescence, to counteract tumorigenesis (Cong & Wright, 2002; Srinivas et al., 2020; Zvereva et al., 2010).
Telomerase can also inactivate tumour suppressor genes or work together with oncogenes to promote the transformation of normal human fibroblasts and epithelial cells into tumorigenic cells. These observations collectively suggest that telomerase plays a significant role in both cellular ageing and tumorigenesis. Given the potential impact of modifying telomerase activity on diagnostic and therapeutic strategies, there is substantial interest in comprehending the mechanisms that regulate telomerase (Cong & Wright, 2002).
Telomere End Replication Problem
The strong link between telomeres and ageing, as well as tumorigenesis, may stem from the "end replication problem". This phenomenon refers to the progressive shortening of telomeres with each successive cell division, caused by incomplete replication at chromosomal ends (Srinivas et al., 2020).
DNA replication is mediated by DNA polymerase, an enzyme capable of synthesising DNA only in the 5' to 3' direction. The process begins with the synthesis of a ribonucleic acid (RNA) primer by primase. This RNA primer serves as a starting point for DNA replication, enabling the identification of the chromosomal region where replication will commence. Upon annealing to the template DNA, the RNA primer provides a free 3'-OH group for the addition of new nucleotides. In leading strand synthesis, proceeding in the 5' to 3' direction, only one primer suffices for continuous synthesis due to nucleotide addition toward the replication fork.
Figure 4
Depiction of the action of primase in DNA replication.
Created using BioRender.com
Conversely, lagging strand synthesis, in the 3' to 5' direction, necessitates multiple primers. These primers elongate into short Okazaki fragments opposite the replication fork direction and are synthesised less efficiently than the leading strand. Following replication, primer degradation leads to internal gaps, which are subsequently filled by the polymerase, Polδ. The newly synthesised DNA fragments are then ligated together to form a continuous strand.
At the 5' end of the lagging strand, a challenge arises where a segment of DNA, equal in size to the RNA primer, is removed. This phenomenon, termed the "end replication problem," occurs when the final RNA primer is removed post-replication. Consequently, a failure to fill the gap resulting from primer degradation at the terminal end leads to the loss of a small DNA segment at the 5′ end of the lagging strand.
Figure 5
Depiction of the end replication problem. Following replication a gap can be soon at the 5' end of the lagging strand.
Created using BioRender.com
The absence of a 3'-OH group following RNA primer removal presents DNA polymerase with a challenge in synthesising the lagging strand's end. Thus, due to the intrinsic nature of DNA polymerase, telomeres undergo shortening by 50-150 base pairs following each S phase of cell division (Lee & Pellegrini, 2022; Srinivas et al., 2020).
A phenomenon termed the Hayflick limit describes that a normal human cell population has a finite number of times it can divide as once this limit is reached, one or more critically shortened telomeres trigger a permanent growth arrest, known as replicative senescence or mortality stage 1 (M1). Certain cells manage to evade replicative senescence by disabling key cell cycle checkpoint genes, like tumour protein p53 (TP53). These survivor cells keep dividing and undergo additional telomere shortening until they reach a subsequent block to proliferation. This subsequent block, referred to as crisis or mortality stage 2 (M2), is marked by widespread cell death triggered by severely shortened and impaired telomeres. Nevertheless, a minority of survivor cells manage to bypass the crisis and sustain telomere length, usually through the activation of telomerase. Ultimately, this leads to a limitless proliferative potential, referred to as cellular immortalization, which typically results in cancer formation (Cong & Wright, 2002; Srinivas et al., 2020).
Telomeres and Ageing
In differentiated or quiescent cells, the stability of telomeres is essential where random double-strand breaks (DSBs) can occur due to damaging factors such as oxidative stress. Normally, cells use DNA Damage Response (DDR) proteins to repair DSBs. However at the telomeres, the repair of these breaks is inhibited by TRF2. In conjunction with Rap1, TRF2 prevents the repair of regular DSBs within the telomeres. This suppression prevents telomere fusion through non-homologous end joining (NHEJ), a potential error during DNA repair that could lead to genomic instability. If DSBs are left unrepaired, the DDR proteins attach to these sites therefore forming telomere-associated foci (TAF). The presence of TAF indicates cellular damage and contributes to the initiation of a cell’s transition into a senescent state (Sławińska & Krupa, 2021). The formation of TAF does not depend on the length of the telomeres or the level of telomerase activity but rather on the age of the organism (Hewitt et al., 2012).
As cells undergo replicative ageing, single-stranded fragments at the telomere ends are exposed, also known as uncapping. This attracts DDR factors to these vulnerable ends, prompting the cell to either enter a state of senescence or initiate apoptosis (Takai et al., 2003). As telomeres continue to shorten and reach a critical threshold, the TRF2 is lost (Herbig et al., 2004). This leads to DDR proteins such as 53BP1, γ-H2AX, RAD17, ATM and Mre11 to accumulate at these unprotected telomeric regions (Takai et al., 2003). These markers also indicate DSBs thus the persistent presence of DDR foci leads to sustained senescence in the cell (Fagagna et al., 2003).
Cells may undergo senescence in response to various stressors and while this state can be advantageous in suppressing tumorigenesis or facilitating tissue repair, it also has implications in the ageing process. When the DDR is activated and the cell starts becoming senescent, certain proteins (proinflammatory cytokines and metalloproteinases) are secreted in increased quantities. This is called the senescence-associated secretory phenotype (SASP). SASP can propagate senescence in neighbouring cells and the progressive accumulation of senescent cells accelerates the ageing process of an organism (Sławińska & Krupa, 2021).
Genetic and Environmental Factors Influencing Telomere Length
Telomere length, influenced by a mix of factors including age, genetics, environment, lifestyle choices, and socioeconomic status, plays an important role in determining overall health and ageing rate. However, gender does not appear to significantly impact telomere loss rate (Shammas, 2011; Andreu-Sánchez et al., 2022).
Various lifestyle behaviours like smoking, obesity, and poor dietary choices can increase the shortening of telomeres, potentially leading to disease or premature death. This accelerated shortening is linked to the early onset of age-related health issues such as heart disease, diabetes, and higher cancer risk. Individuals with shorter leukocyte telomeres compared to the average length are at a significantly higher risk of suffering from heart attacks (Shammas, 2011).
Obesity contributes to heightened oxidative stress and DNA damage, possibly due to imbalanced production of adipocytokines. Stress prompts the adrenal gland to release glucocorticoid hormones, which can decrease levels of antioxidant proteins, thereby heightening oxidative DNA damage and speeding up telomere shortening. The rapid shortening of telomeres can impact health and longevity on multiple fronts. Shorter telomeres may trigger genomic instability by causing fusion between chromosomes, potentially resulting in cancer development. (Shammas, 2011).
In humans various genes have been associated with telomere length and G-rich overhangs, such as telomere repeat factor 2 (TRF2). Inhibition of binding of TRF2 to telomeres results in the dysfunction of telomeres and the dysregulation of telomere length, through apoptosis of cells. This shows that TRF2 has a protective role in telomeres. When telomeres are not functioning properly, G-overhangs might be absent, resulting in the prevention of T-loops formation and the generation of abnormal chromosomes with two centromeres. This might have an effect on cell division, contributing to apoptosis or premature ageing syndromes, such as ataxia telangiectasia (Njajou et al., 2007; Saldanha et al., 2003).
Research into the genetic determinants of telomere length has been extensive. Twin studies suggest that heritable factors may contribute up to 80% of the variation in telomere length between individuals. Recent genome-wide association studies (GWAS) of European descent and the Chinese population have pinpointed genetic variants at various chromosome loci which are associated with telomere length (Weng et al., 2016; Srinivas et al., 2020).
Diseases and Telomeres
As mentioned above, telomere length is associated with the risk of various diseases, including chronic obstructive pulmonary disease (COPD), cardiovascular diseases, genetic disorders known as telomere diseases and other conditions (Weng et al., 2016).
Various diseases affecting lung function are associated with dysfunctional telomeres and the accumulation of senescent cells. Fibrosis, for instance, is closely linked to telomere shortening, triggering a DDR and cellular senescence. This results in the build-up of Telomere Dysfunction-Associated Foci (TAFs) and senescence markers within the lungs, activating the Senescence-Associated Secretory Phenotype (SASP) as the disease progresses (Rossiello et al., 2022) .
Chronic Obstructive Pulmonary Disease (COPD) is characterised by inflammation in lung tissues and airways, along with chronic remodelling of bronchi, leading to disruption of interalveolar septa and emphysema. Small airway epithelial cells from COPD patients exhibit elevated levels of TAFs and senescence markers compared to unaffected individuals (Rossiello et al., 2022).
Cardiovascular diseases (CVDs) are profoundly affected by ageing and telomere dynamics. Telomere shortening and damage play critical roles in heart disease development and serve as indicators of therapeutic outcomes. Ageing hearts typically experience cardiomyocyte hypertrophy and fibrosis, leading to increased ventricular stiffness and impaired function. TAFs emerge in post-mitotic cardiomyocytes during physiological ageing, contributing to cardiac hypertrophy and fibrosis through the induction of SASP (Rossiello et al., 2022.
Atherosclerosis involves the accumulation of artery plaques containing vascular smooth muscle cells (VSMCs) that can lead to thrombosis and myocardial infarction. VSMCs in atherosclerotic plaques exhibit cellular senescence markers and markedly shorter telomeres compared to healthy vessels from the same individual. Telomere dysfunction induced by mutant TRF2 expression in VSMCs accelerates atherosclerosis progression (Rossiello et al., 2022).
Dyskeratosis congenita (DC) is a hereditary condition characterised by bone marrow failure, various physical abnormalities, such as abnormal skin pigmentation and nail dystrophy, and increased risk of cancer. DC and similar conditions related to telomere biology arise from genetic mutations disrupting the normal maintenance of telomeres. DC mutations were found in several genes including Dyskerin Pseudouridine Synthase 1 (DKC1), TERC, TERT, Nucleolar Protein 10 (NOP10), Nuclear Protein H2 (NHP2), and TINF2. These genes are responsible for producing elements of either the telomerase holoenzyme or the telomere shelterin complex that are important for telomere maintenance and protection. Alterations in these genes can result in a range of clinical symptoms, from DC itself to conditions like bone marrow failure, pulmonary fibrosis, and other medical complications (Kirwan & Dokal, 2009; Savage, 2022).
Cancer and Telomeres
In cancer development, the role of telomeres and their dysfunction is vital. Oncogenic alterations enable certain cells to avoid senescence, leading to an extended period of proliferation. Yet, as multiple critically shortened telomeres reach crisis, marked by complete replicative senescence, chromosome end-to-end fusions, and apoptosis, a cascade of breakage-fusion-bridge cycles results. These cycles cause the fusion of telomere-deficient sister chromatids, forming chromatin bridges that are eventually pulled apart during anaphase, resulting in uneven derivative chromosomes and genomic instability. Although crisis culminates in extensive cell death, rare cells may evade this fate, maintaining stable albeit shortened telomeres for continued growth, ultimately progressing to malignancy (Jafri et al., 2016).
In cancer, cells achieve continuous proliferation through the activation or upregulation of the silent hTERT gene. While hTERT is typically silenced in somatic cells, its expression is markedly elevated in approximately 90% of human cancers due to both genetic and epigenetic factors. The precise mechanisms governing hTERT activation remain unclear, primarily attributed to mutations in the hTERT promoter, alterations in alternative splicing of hTERT pre-mRNA, hTERT amplification, epigenetic modifications like TERT promoter methylation, and disruption of telomere position effect (TPE) machinery (Starkweather et al., 2014; Jafri et al., 2016; Trybek et al., 2020).
In a subset of tumours, estimated at 5-15%, an alternative DNA recombination mechanism known as alternative lengthening of telomeres (ALT) is employed. This phenomenon is frequently observed in tumours originating from mesenchymal or epithelial tissues, such as bone, soft tissues, neuroendocrine systems, and the nervous system (Trybek et al., 2020).
Extensive research attempts have focused on solving the mechanisms leading to TERT expression and telomerase activity in cancer. The dysregulation of telomerase and telomere genes is implicated in various syndromes, spanning from dyskeratosis congenita to progressive forms of idiopathic pulmonary fibrosis, underscoring the broader implications of telomere dysfunction in disease pathology (Trybek et al., 2020).
Applications of Telomeres in Health Research
Telomere extension as a therapeutic strategy is a promising field in biomedical research to treat age related diseases. The idea for this strategy is to artificially elongate telomeres through molecular processes such as TERT expression with the aim of decelerating or even reversing cellular ageing. This could potentially improve the rate of age-related pathologies (Bär & Blasco, 2016).
Telomere extension therapies
Figure 6
Depiction of the action of telomerase, elongating the telomeres
Created in BioRender.com
Experimental models, particularly in mice, have shown that overexpression of telomerase can not only extend telomeres but also reduce age-related degeneration, thereby increasing lifespan (Jaskelioff et al., 2010). This is also shown in a study where the systemic delivery of the TERT gene has delayed the onset of age-related pathologies and extended lifespan in mice without increasing the risk of cancer formation (Bernardes de Jesus et al., 2012). However, telomerase therapies come with a set of risks. Although there are studies that have managed to exploit telomerase without inducing cancer, there is still an increased risk of cancer because it enables the limitless replicative potential of precancerous cells. Research is also focused on developing safe strategies for transient and controlled telomerase activation in order to mitigate the risk of adverse effects (Tomás-Loba et al., 2008). For example, a TERT gene therapy that uses non-integrative vectors was studied for its ability to transiently extend telomeres with a limited number of cell divisions which should theoretically reduce cancer risks (Bernardes de Jesus et al., 2012).
Conclusion
In conclusion, telomeres have an important role in cellular and DNA integrity and they also have implications in health and disease. They protect chromosome ends from degradation therefore regulating cellular ageing and lifespan. They are the main character in phenomenons like the end replication problem and telomerase activity. As telomeres shorten with each cell division, they eventually become critically short which triggers the cell to enter a state of senescence or apoptosis. This is being looked at by research as the biological clock that influence ageing and disease susceptibility.
Telomerase plays a major role in elongating telomeres and reversing DNA loss during replication in order to balance genomic stability with potential oncogenic risks if dysregulated. The interaction of telomere-associated proteins, particularly the shelterin complex, with repair mechanisms further demonstrates their importance in maintaining genomic stability. Factors such as lifestyle, environment and genetics also have an influence on telomere length therefore providing insight into potential strategies on how to mitigate age-related diseases and increase longevity. This understanding of telomere dynamics opens possibilities for targeted therapies in ageing and disease management.
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