Telomeres and Telomerase in Ageing and Cancer


Telomeres are protective structures that cap the ends of linear chromosomes. In humans, they are made of a repetitive DNA (deoxyribonucleic acid) sequence, (TTAGGG)n, and associated proteins. Because DNA polymerases are unable to completely replicate the ends of linear chromosomes, telomeres shorten each time cells divide. This gradual shortening of the telomeres limits their cellular lifespan and contributes to the ageing process. During cancer development, this obstacle to immortality is almost always bypassed by the overexpression of telomerase, a specialised reverse transcriptase that functions to add back telomeric repeats to telomeres. In humans, its expression is limited to rare stem cells of renewal tissues, but a notable exception has been its overexpression in the great majority of cancers. Accordingly, telomerase is being developed as both a novel marker for the detection of cancer cells and a novel target for the treatment of cancers. Herein, we discuss the role of telomeres and telomerase in cancer and ageing, with the emphasis on potential future applications in the treatments of cancers and age‐related diseases.

Key Concepts

  • Telomeres are protective structures that cap the ends of chromosomes.
  • Human telomeres are made of TTAGGG DNA repeats and associated proteins.
  • Because of ‘end replication problems’, telomeres shorten each time cells divide, and this shortening limits cellular lifespan and contributes to the ageing process.
  • Telomerase is a specialised reverse transcriptase that functions to add back telomeric repeats to the ends of telomeres, thereby extending cellular lifespan.
  • Telomerase expression in humans is limited to rare stem cells of renewal tissues (gastrointestinal track, blood and skin).
  • Telomerase is almost always aberrantly overexpressed in cancer. This overexpression is detected in 85% of all cancers, irrespective of the tumour type.
  • Telomerase is being developed as a marker to allow the detection of cancer cells in otherwise telomerase‐negative normal tissues.
  • Inhibitors of telomerase are being developed to limit tumour growth and reduce the incidence of recurrences following conventional cancer therapy.
  • Strategies for transient telomerase reactivation are also being developed for the treatment of degenerative diseases and age‐related diseases.

Keywords: telomere; telomerase; cancer; ageing; senescence; and cellular immortality

Figure 1. The structure of human telomeres. (a) Human telomeres are made of telomeric DNA (deoxyribonucleic acid) repeats and associated protein complexes. Among these complexes are Shelterin complexes and subcomplexes that bind preferentially to the ss/ds‐telomeric DNA junction, in addition to duplex telomeric DNA. Other complexes bind to the single‐stranded 3′‐overhang and include the POT1/TPP1 heterodimer, CST (CTC1‐STN1‐TEN1) complex and RPA (replication protein A) complex. (b) Telomeres can fold into a T loop, which involves a folding of the telomere onto itself and the invasion of the 3′‐overhang into upstream duplex telomeric DNA.
Figure 2. Biochemical activity of telomerase. The enzyme telomerase is made of two essential subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA (hTR). The hTR RNA contains a short sequence, complementary to that of the telomeric repeats (5′‐CUAACCCUAAC‐3′), which the enzyme uses as a template. As the enzyme associates with the telomeres, this sequence hybridises with the 3′ overhang that caps all telomeres. The protein hTERT, acting as a reverse transcriptase, then uses the telomere as a primer and hTR as a template to synthesise a six‐base telomeric repeat. The enzyme is highly processive and can add many repeats to the same DNA substrate through cycles of synthesis and translocation.
Figure 3. Senescence and crisis. Most somatic human cells lack telomerase and, as a consequence, shorten their telomeres at each round of cell divisions. When the shortest telomere reaches a threshold size, senescence (M1 or mortality stage 1) is triggered. The cell cycle arrest that characterises senescence is maintained by the activities of p53 and RB, and can therefore be bypassed by the loss of these tumour suppressors. Cells that have overcome M1 continue to shorten their telomeres as they divide, until the induction of crisis (M2 or mortality stage 2). M2 is characterised by massive cell death and is due to terminal telomere shortening. Rare cells can escape M2 to give rise to immortal clones, but only after telomeres have become stabilised through either telomerase (hTERT) expression or activation of the ALT (alternate lengthening of telomeres) pathway.


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Further Reading

Flores I and Blasco MA (2010) The role of telomeres and telomerase in stem cell aging. FEBS Letters 584: 3826–3830. PMID: 20674573.

Maciejowski J and de Lange T (2017) Telomeres in cancer: tumour suppression and genome instability. Nature Reviews. Molecular Cell Biology 18: 175–186. PMCID: PMC5589191.

Njajou OT, Hsueh WC, Blackburn EH, et al. (2009) Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population‐based cohort study. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 64: 860–864. PMCID: PMC2981462.

Opresko PL and Shay JW (2017) Telomere‐associated aging disorders. Ageing Research Reviews 33: 52–66. PMID: 27215853.

Ouellette MM, Wright WE and Shay JW (2011) Targeting telomerase‐expressing cancer cells. Journal of Cellular and Molecular Medicine 15: 1433–1442. PMCID: PMC3370414.

Wright WE and Shay JW (2000) Telomere dynamics in cancer progression and prevention: fundamental differences in human and mouse telomere biology. Nature Medicine 6: 849–851. PMID: 10932210.

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Ouellette, Michel M(Feb 2018) Telomeres and Telomerase in Ageing and Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006067.pub3]