By Taylor Woetzel
In 2009, the Nobel Prize in Physiology or Medicine was awarded for groundbreaking discoveries of how telomeres and telomerase protect the ends of chromosomes.1 Telomeres are the repetitive nucleotide sequences that cap the ends of chromosomes and protect them from deterioration or fusion with neighboring chromosomes. Telomerase, the enzyme that maintains telomeres, is comprised of two components: a functional RNA component called hTERC in humans, and a catalytic protein with reverse transcriptase activity called hTERT.2 By capping chromosome ends, telomeres prevent chromosomal instability which could lead to aneuploidy and diseases such as cancer and premature aging disorders,1 which implicate telomerase dysregulation in an opposing fashion.
Despite their protective nature, telomere size is not constant. Telomere shortening occurs with each cell division due to the “end-replication problem”, where DNA polymerases cannot fully replicate the 3′ end of linear chromosomes.2 As a result, small fragments of telomeric DNA are lost during each cycle of cell division, which prevents non-telomeric coding DNA from being lost instead. [BF1] In normal somatic cells, telomerase activity is minimal or absent, which prevents telomere elongation. The discovery of the Hayflick limit by Leonard Hayflick in 1961 revealed that human cells have a finite capacity for division, typically around 40 to 60 times, due to progressive telomere shortening. This phenomenon, referred to as “replicative senescence”, has been proposed to act as a protector of cellular maintenance by acting as a powerful tumor-suppressing mechanism, preventing the accumulation of potentially oncogenic mutations through the limitation of cellular longevity.3
Telomere maintenance is critical for cancer cell survival and proliferation. At the Hayflick limit, one or more critically shortened telomeres trigger a permanent growth arrest known as replicative senescence or mortality stage 1 (M1).2 Pre-oncogenic cells that escape replicative senescence, typically by inactivation of a critical cell cycle checkpoint gene like p53, continue to divide and suffer further telomere loss until they reach a second proliferative block, crisis, or mortality stage 2 (M2). Crisis is characterized by massive cell death that is triggered by critically short and dysfunctional telomeres. Most rare survivor cells that escape from crisis do so through the regained maintenance of telomeres, in most cases by activation of telomerase.4 In fact, approximately 90% of human cancers contain reactivated telomerase that contributes to the unlimited proliferative capacity that enables tumor formation.
Telomerase activation in cancer involves complex regulatory mechanisms, including transcriptional, post-transcriptional, and epigenetic changes.4 For instance, mutations in the hTERT promoter region have been identified in various cancers, leading to increased telomerase expression and activity. These mutations can create new binding sites for transcription factors, enhancing the transcription of hTERT. As a result, telomerase levels increase in the cells, promoting their ability to divide indefinitely. This increased transcriptional activity is crucial for the maintenance of telomere length in cancer cells, allowing them to bypass the Hayflick limit that would otherwise limit their growth. Post-transcriptional mechanisms also play a significant role in telomerase activation in cancer.4 Alternative splicing of hTERT pre-mRNA can lead to the production of different isoforms of the enzyme, some of which are more active or stable than others. This splicing variability allows cancer cells to modulate telomerase activity to meet their needs for sustained proliferation.5 Additionally, changes in mRNA stability and translational efficiency can further regulate the levels of telomerase in cancer cells. Epigenetic modifications, such as DNA methylation and histone modifications, add another layer of regulation for telomerase activation, as exemplified by increased expression of hTERT due to hypomethylation of the hTERT promoter region.6 Histone modifications, such as acetylation and methylation, can alter the chromatin structure, making the hTERT gene more accessible to the transcriptional machinery. These epigenetic changes can disrupt the normal repression mechanisms of telomerase, contributing to its reactivation in cancer cells.
At the opposite extreme of telomere dysregulation, we encounter progeroid syndromes, a group of rare genetic disorders characterized by accelerated aging.7 Unlike in cancer, where telomerase is upregulated, certain progeroid syndromes are marked by downregulated telomerase activity and accelerated telomere attrition.8 This telomere shortening leads to premature cellular senescence and apoptosis, contributing to the clinical manifestations of these syndromes.
Hutchinson-Gilford Progeria Syndrome (HGPS) is one of the most well-known progeroid syndromes, caused by mutations in the LMNA gene that encodes lamin A, a nuclear envelope protein.9 These mutations result in the production of a truncated, dysfunctional form of lamin A, known as progerin, which disrupts nuclear architecture and impairs DNA repair mechanisms, leading to accelerated telomere shortening and cellular aging. Patients with HGPS exhibit symptoms of early aging, such as hair loss, skin atrophy, cardiovascular diseases, and a significantly reduced lifespan. Werner syndrome (WS), another progeroid syndrome, is caused by mutations in the WRN gene, which encodes a RecQ helicase involved in DNA repair and telomere maintenance. WRN deficiency leads to increased telomere attrition and genomic instability, manifesting in premature aging, cataracts, diabetes, osteoporosis, and a higher predisposition to cancer.10 Another progeroid syndrome, Dyskeratosis congenita, is characterized by abnormal nails, reticular skin pigmentation, oral leukoplakia, and high risk of cancer, and is also associated with defective telomerase components.11 Mutations in the DKC1 gene, which encodes dyskerin, a protein essential for the stabilization and activity of hTERC, are commonly identified in cases of dyskeratosis congenita,8 further demonstrating the detrimental consequences of telomerase disruption.
Compared to its role in cancer, aberrant telomerase function in progeroid syndromes represents the opposing extreme in telomerase dysfunction. This dual role, with dysregulation contributing to cancer by enabling unlimited cell proliferation and to progeroid syndromes by accelerating cellular aging, shows the importance of balanced telomere maintenance activity in health and disease. As such, therapeutics targeting telomerase are being developed to inhibit its activity in cancer treatment, aiming to limit the unchecked growth of cancer cells.12 Conversely, enhancing telomerase activity holds potential for treating progeroid syndromes and has been demonstrated to improve hallmarks of progeria in HGPS cells.13 As we advance targeting telomerase holds the potential for profound and far-reaching implications across various diseases, driven by the intricate and multifaceted nature of telomere maintenance.
References
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