Telomerase: Structure and Function


In contrast to normal cells, tumour cells generally have short telomere lengths and show no continuing loss of telomere length with successive cell divisions, suggesting that telomere stability may be required for cells to escape from replicative senescence and proliferate indefinitely. Most, but not necessarily all, malignant tumours are immortal to sustain their growth, thus, the cellular ribonucleoprotein (reverse transcriptase) enzyme complex termed telomerase may be a rate‐limiting step required for the continuing proliferation of advanced cancers. Telomerase, the enzyme that completes deoxyribonucleic acid (DNA) replication at the termini of eukaryotic chromosomes, is an important factor in DNA replication, chromosomal stability and tumorigenesis.

In human tumours, telomere length is maintained by a balance between processes that lengthen telomeres (telomerase) and processes that shorten telomeres (lack of complete lagging DNA strand synthesis ‘end replication problem’ and other end processing events). Telomerase stabilises telomere length by adding TTAGGG repeats onto the telomeric ends of the chromosomes, thus compensating for the continued erosion of telomeres that occurs in its absence. As telomerase is expressed in almost all human cancers, approaches for inhibiting telomerase as a target for cancer therapeutics are currently progressing through clinical trials.

Key Concepts:

  • Telomeres, the ends of human chromosomes progressively shorten throughout life in all dividing human cells and when critically shortened become ‘uncapped’ leading to a DNA damage signal and then undergo growth arrest termed replicative senescence (cell ageing).

  • A hallmark of cancer cells is unlimited cell growth.

  • Advanced cancer cells accomplish immortality almost universally by activating or upregulating the ribonucleoprotein complex termed telomerase.

  • Telomerase is composed of two essential components, TERT (reverse transcriptase component) and TERC (functional or template RNA that recognises the ends of chromosomes).

  • Telomerase is expressed during early human development and remains silent in almost all human tissues except transiently amplified stem cells throughout life.

  • Approximately 90% of all human cancers express telomerase activity.

  • A small fraction of human tumours do not express telomerase and some of these may engage a DNA recombination mechanism to maintain telomeres termed ALT, alternative lengthening of telomeres.

  • Introduction of hTERT into normal telomerase silent cells is sufficient to immortalise cells in appropriate culture conditions without the cells becoming cancerous.

  • As telomerase is almost a universal oncology target, inhibiting telomerase should be a potent anticancer therapeutic target.

Keywords: telomerase; telomeres; senescence; ageing; immortal; cancer

Figure 1.

Simplified model of telomeric addition. After recruitment of the telomerase holoenzyme to telomeric DNA, the template domain of the telomerase RNA (hTER) allows complementary base pairing to existing hexameric repeats (a). Reverse transcription by the hTERT continues until the RNA template sequence is fully replicated, at which time the enzyme complex must translocate to continue synthesis of the next repeat (b). In the ciliate Tetrahymena, this translocation is accompanied by a pause in polymerisation, and telomerase can maintain processive synthesis for an average of roughly 520 nt before dissociating from the DNA substrate (Greider, ). Here, an oligomer of several RNA subunits is shown to illustrate how the enzyme might extend telomeric DNA using multiple active sites.

For an updated understanding of how telomerase adds back DNA sequences either processively or distributively, see Zhao et al. . Modified with permission from Greider .


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Further Reading

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Nakamura TM, Morin GB, Chapman KB et al. (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277: 955–959.

Shay JW, Reddel RR and Wright WE (2012) Cancer and Telomeres – An ALTernative to telomerase. Science 336: 1388–1389.

Shay JW and Wright WE (1996) The reactivation of telomerase activity in cancer progression. Trends in Genetics 12: 129–131.

Shay JW and Wright WE (2005) Mechanism‐based combination telomerase inhibition therapy. Cancer Cell 7: 1–2.

Shay JW and Wright WE (2006) Telomerase therapeutics for cancer: challenges and new directions. Nature Reviews in Drug Discovery 5: 477–584.

Shay JW and Wright WE (2011) Role of telomeres and telomerase in cancer. Seminars in Cancer Biology 21: 349–353.

Wright WE and Shay JW (2005) Telomere‐binding factors and general DNA repair. Nature Genetics 37: 116–118.


Telomerase‐associated protein 1 (TEP1); LocusID: 7011. LocusLink:

Telomerase‐associated protein 1 (TEP1); MIM number: 601686. OMIM:‐post/Omim/dispmim?601686.

Telomerase reverse transcriptase (TERT); LocusID: 7015. LocusLink:

Telomerase reverse transcriptase (TERT); MIM number: 187270. OMIM:‐post/Omim/dispmim?187270.

Telomerase RNA component (TERC); LocusID: 7012. LocusLink:

Telomerase RNA component (TERC); MIM number: 602322. OMIM:‐post/Omim/dispmim?602322.

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Shay, Jerry W(Oct 2013) Telomerase: Structure and Function. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006167.pub2]