Skip to main content
Log in

An introduction to telomeres and telomerase

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

It is now more than a dozen years since the enzyme telomerase was discovered, and since that time, key studies have characterized the structural components of the enzyme and the associated telomeric proteins. Since the original discovery of telomerase, a clear association with cancer has been demonstrated. In normal somatic cells the telomeres at the ends of chromosomes shorten with every cell division, whereas in cancer cells telomere length is often maintained by reactivation of the enzyme telomerase. These discoveries have led to the proposal that telomerase expression can be used as a helpful marker for diagnostic and prognostic purposes in humans. Another area of research that has developed as a result of improving knowledge and understanding of the role of telomerase in malignancy is that of cancer therapeutics. This article is an introduction to the field of telomere and telomerase research, with an introduction to recent attempts to develop novel cancer treatments based on telomerase structure and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Blackburn, E.H. (1991). Structure and function of telomeres. Nature 350, 569–573.

    Article  PubMed  CAS  Google Scholar 

  2. Zakian, V.A. (1989). Structure and function of telomeres. Ann. Rev. Gene. 23, 579–604.

    Article  CAS  Google Scholar 

  3. Moyzis, R.K, Buckingham JM, Cram L.S., et al. (1988). A highly conserved repetitive DNA sequence (TTAG GG)n, present at the telomeres of human chromosomes. Proc. Natl. Acad. Sci. USA 85, 6622–6626.

    Article  PubMed  CAS  Google Scholar 

  4. Brown, W.R.A. (1989). Molecular cloning of human telomeres in yeast. Nature 338, 774–776.

    Article  PubMed  CAS  Google Scholar 

  5. Cross, S.H., Allshire, R.C., McKay, S.J., et al. (1989). Cloning of human telomeres by complementation in yeast. Nature 338, 771–774.

    Article  PubMed  CAS  Google Scholar 

  6. de Lange, T., Shiue, L., Myers, R.M., et al. (1990). Structure and variability of human chromosome ends. Mol. Cell Biol. 10, 518–527.

    PubMed  Google Scholar 

  7. Hastie, N.D., Dempster, M., Dunlop, M.G., et al. (1990). Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868.

    Article  PubMed  CAS  Google Scholar 

  8. Henderson, E. (1995) in Telomeres. (Blackburn, E.H. and Greider, C. W., eds.) Cold Spring Harbour Laboratory Press, Cold Spring Harbor, NY, pp. 11–34.

    Google Scholar 

  9. Cooke, H.J. and Smith, B.A. (1986). Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harb. Symp. Quant. Biol. 51, 213–219.

    PubMed  CAS  Google Scholar 

  10. Prowse, K.R. and Greider, C.W. (1995). Developmental and tissue specific regulation of mouse telomerse and telomere length. Proc. Natl. Acad. Sci. USA 92, 4818–4822.

    Article  PubMed  CAS  Google Scholar 

  11. Allshire, R.C., Dempster, M., and Hastie, N.D. (1989). Human telomeres contain at least three types of G-rich repeats distributed non-randomly. Nucleic Acid Res. 17, 4611–4627.

    Article  PubMed  CAS  Google Scholar 

  12. Lansdorp, P.M., Verwoerd, N.P., van de Rijke, F.M. et al. (1996). Heterogeneity in telomere length of human chromosomes. Human Mol. Genet. 5, 685–691.

    Article  CAS  Google Scholar 

  13. Henderson, S., Allsopp, R., Spector, D., et al. (1996). In situ analysis of changes in telomere size during replicative ageing and cell transformation. J. Biol. Chem. 134, 1–12.

    CAS  Google Scholar 

  14. Buchkovich, K.J. and Greider, C.W. (1996). Telomerase regulation during entry into the cell cycle in normal human T cells. Mol. Biol. Cell 134, 1443–1454.

    Google Scholar 

  15. Nakamura, T.M. and Cech, T.R. (1998). Reversing time: origin of telomerase. Cell 92, 587–590.

    Article  PubMed  CAS  Google Scholar 

  16. Weng, N.P., Levine, B.L., June, C.H., and Hodes, R.J. (1996). Regulated expression of telomerase activity in human T lymphocyte development and activation. J. Exp. Med. 183, 2471–2479.

    Article  PubMed  CAS  Google Scholar 

  17. Holt, S.E., Wright, W.E., and Shay, J.W. (1996). Regulation of telomerase activity in immortl cell lines. Mol. Cell Biol. 16, 2932–2939.

    PubMed  CAS  Google Scholar 

  18. Shay, J.W. (1998). Telomerase in cancer: Diagnostic, prognostic and therapeutic implications. Cancer J. Sci. Am. 4, S1, S26-S34.

    PubMed  Google Scholar 

  19. Achi, M.V., Ravindranath, N., and Dym, M. (2000). Telomere length in male germ cells is inversely correlated with telomerase activity. Biol. Reprod. 63, 591–598.

    Article  PubMed  CAS  Google Scholar 

  20. Weinrich, S.l., Pruzan, R., Ma, L., et al. (1997). Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT. Nat. Genet. 17, 498–502.

    Article  PubMed  CAS  Google Scholar 

  21. Greider, C.W. and Blackburn, E.H. (1985). Identification of a specific telomere terminal transferase activity in tetrahymena extracts. Cell 43, 405–413.

    Article  PubMed  CAS  Google Scholar 

  22. Shippen-Lentz, D. and Blackburn, E.H. (1990). Functional evidence for an RNA template in telomerase. Science 269, 546–552.

    Article  Google Scholar 

  23. Blasco, M.A., Funk, W., Villeponteau. B., and Greider, C.W. (1995). Functional characterization and developmental regulation of mouse telomerase RNA. Science 269, 1267–1270.

    Article  PubMed  CAS  Google Scholar 

  24. Feng, J., Funk, W.D., Wang, S.S., et al. (1995). The RNA component of human telomerase. Science 269, 1236–1241.

    Article  PubMed  CAS  Google Scholar 

  25. Nakamura, T.M., Morin, G.B., Chapman, K.B., et al. (1997). Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959.

    Article  PubMed  CAS  Google Scholar 

  26. Soder, A.I., Hoare, S.R., Muir, S., et al. (1997). Amplification, increased dosage and in situ expression of the telomerase RNA gene in human cancer. Oncogene 14, 1013–1021.

    Article  PubMed  CAS  Google Scholar 

  27. Soder, A.I., Hoare, S.F., Muire, S., et al. (1997). Mapping of the gene for the mouse telomerase RNA component, Terc, to chromosome 3 by fluorescence in situ hybridization and mouse chromosome painting. Genomics 41, 293–294.

    Article  PubMed  CAS  Google Scholar 

  28. Lingner, J., Hughes, T.R., Shevchenko, A., et al. (1997). Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567.

    Article  PubMed  CAS  Google Scholar 

  29. Meyerson, M., Counter, C.M., Eaton, E.N., et al. (1997). hEST2, the putative human telomerase catalytic subunit gene, is upregulated in tumor cells and during immortalization. Cell 90, 785–795.

    Article  PubMed  CAS  Google Scholar 

  30. Killian, A., Bowtell, D.D.L., Abud, H.E., et al. (1997). Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Human Mol. Genet. 6, 2011–2019.

    Article  Google Scholar 

  31. Harrington. L., McPhail, T., Mar, V., et al. (1997). A mammalian telomerase associated protein. Science 275, 973–977.

    Article  PubMed  CAS  Google Scholar 

  32. Zhao, J-.Q., Hoare, S.F., McFarlane, R., et al. (1998). Cloning and characterization of human and mouse telomerase RNA gene promoter sequences. Oncogene 16, 1345–1350.

    Article  PubMed  CAS  Google Scholar 

  33. Bachand, F. and Autexier, C. (2001). Functional regions of human telomerase reverse transcriptase and human telomerase RNA required for telomerase activity and RNA-protein interactions. Mol. Cell. Biol. 21, 1888–1897.

    Article  PubMed  CAS  Google Scholar 

  34. Yi, X.M., White, D.M., Aisner, D.L., et al. (2000). An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity. Neoplasia 2, 433–440.

    Article  PubMed  CAS  Google Scholar 

  35. Koyanagi, Y., Kobayashi, D., Yajima, T., et al. (2000). Telomerase activity is down regulated via decreases in hTERT mRNA but not TEP1 mRNA or hTERC during the differentiation of leukemic cells. Anticancer Res. 20, 773–778.

    PubMed  CAS  Google Scholar 

  36. Krams, M., Claviez, A., Klapper, W., et al. (2000). Upregulated telomerase activity and high mRNA levels of the catalytic telomerase subunit hTERT in Hodgkin and Reed Sternberg cells. Blood 96, 3142.

    Google Scholar 

  37. Ouellette, M.M., Aisner, D.L., Savre-Train, I., et al. (1999). Telomerase activity does not always imply telomere maintenance. Biochem. Biophys, Res. Comm, 254, 795–803.

    Article  CAS  Google Scholar 

  38. Steensel, van B. and de Lange, T. (1997). Control of telomere length by the human telomeric protein TRF1. Nature 385, 740–743.

    Article  PubMed  Google Scholar 

  39. Smith, S., Giriat, I., Schmitt, A., and de Lange, T. (1998). Tankyrase, a poly(ADP-ribose) polymerase at human telomeres. Science 282, 1484–7.

    Article  PubMed  CAS  Google Scholar 

  40. Steensel, van B., Smogorzewska, A., and de Lange, T. (1998). TRF2 protects human telomeres from end to end fusions. Cell 92, 401–483.

    Article  PubMed  Google Scholar 

  41. Yokoyama, Y., Takahashi, Y., Shinohara, A., et al. (2000). The 5 ′-end of hTERT mRNA is a good target for hammerhead ribozyme to suppress telomerase activity. Bichem. Biophs. Res. Comm. 273, 316–321.

    Article  CAS  Google Scholar 

  42. Harley, C.B. (1991). Telomere loss: mitotic clock or genetic time bomb? Mutation Res. 256, 271–282.

    Article  PubMed  CAS  Google Scholar 

  43. Avilion, A.A., Harrington, L.A., and Greider, C.W. (1992). Tetrahymena telomerase RNA levels increase during macronuclear development. Dev. Genet. 13, 80–86.

    Article  PubMed  CAS  Google Scholar 

  44. Price, C.M., Adams, A.K., and Vermeesch, J.R. (1994). Accumulation of telomerase RNA and telomere protein transcripts during telomere synthesis in Euplotes. J. Eukaryot. Microbio. 41, 267–275.

    Article  CAS  Google Scholar 

  45. Villeponteau, B. (1996). The RNA components of human mouse telomerases. Cell Dev. Biol. 7, 15–21.

    Article  CAS  Google Scholar 

  46. Bryan, T.M., Marusic, L., Bacchetti, S., et al. (1997). The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. Human Mol. Genet. 6, 921–926.

    Article  CAS  Google Scholar 

  47. Blasco, M., Lee, H.-W., Hande, M., et al. (1997). Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34.

    Article  PubMed  CAS  Google Scholar 

  48. Lee, H.-W., Blasco, M.A., Gottlieb, G.J, et al. (1998). Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574.

    Article  PubMed  CAS  Google Scholar 

  49. Bodnar, A.G., Ouellette, M., Frolkis, M., et al. (1998). Extension of life-span by introduction of telomerase into no.mal cells. Science 279, 349–352.

    Article  PubMed  CAS  Google Scholar 

  50. Bacchetti, S. (1996). Telomere dynamics and telomerase activity in cell senescence and cancer. Cell Dev. Biol. 7, 31–39.

    Article  CAS  Google Scholar 

  51. Shay, J.W. and Bacchetti, S. (1997). A survey of telomerase activity in human cancer. Eur. J. Cancer 33, 787–791.

    Article  PubMed  CAS  Google Scholar 

  52. Kim, N.W., Piatyszek, M.A., Prowse, K.R., et al. (1994). Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2014.

    Article  PubMed  CAS  Google Scholar 

  53. Ballon, G., Trentin, L., de Rossi, A., and Semenzato, G. (2001). Telomerase activity and clinical progression in chronic lymphoproliferative disorders of B-cell lineage. Leuk. Lymphoma 41, 35.

    Article  PubMed  CAS  Google Scholar 

  54. Bialkowska-Hobrzanska, H., Bowles, L., Bukala, B., et al. (2000). Comparison of human telomerase reverse transcriptase messenger RNA and telomerase activity as urine markers for diagnosis of bladder carcinoma. Mol. Diag 5, 267–277.

    Article  CAS  Google Scholar 

  55. Chang, J.T.C., Liao, C.T., Jung, S.M., et al. (2000). Telomerase activity is frequently found in metaplastic and malignant human nasopharyngeal tissues. Br. J. Cancer 82, 1946–1951.

    Article  PubMed  CAS  Google Scholar 

  56. Choi, L.M.R., Kim, N.W., Zuo, J.J., et al. (2000). Telomerase activity by TRAP assay and telomerase RNA (hTR) expression are predictive of outcome in neuroblastoma. Med. Pediatr. Oncol. 35, 647–650.

    Article  PubMed  CAS  Google Scholar 

  57. Hiyama, E., Saeki, T., Hiyama, K., et al. (2000). Telomerase activity as a marker of breast carcinoma in fine-needle aspirated samples. Cancer Cytopathol. 90, 235–238.

    CAS  Google Scholar 

  58. Poremba, C., Willenbring, H., Hero, B., et al. (1999). Telomerase activity distinguishes between neuroblastomas with good and poor prognosis. Ann. Oncol. 10, 715–721.

    Article  PubMed  CAS  Google Scholar 

  59. Uchida, N., Otsuka, T., Arima, F., et al. (1999). Correlation of telomerase activity with development and progression of adult T-cell leukemia. Leukemia Res. 23, 311–316.

    Article  CAS  Google Scholar 

  60. Usselmann, B., Newbold, M., Morris, A., and Nwokolo, C.U. (2001). High tumour telomerase activity correlates with shortened patient survival and more advanced tumour stage in gastric but not in oesophageal adenocarcinoma. Gut 48, 176.

    Article  Google Scholar 

  61. Yan, P., Coindre, J.M., Benhattar, J., et al. (1999). Telomerase activity and human telomerase reverse transcriptase mRNA expression in soft tissue tumors: Correlation with grade, histology, and proliferative activity. Cancer Res. 59, 3166–3170.

    PubMed  CAS  Google Scholar 

  62. Yoo, J. and Robinson, R.A. (2000). Expression of telomerase activity and telomerase RNA in human soft tissue sarcomas. Arch. Pathol. Lab. Med. 124, 393–397.

    PubMed  CAS  Google Scholar 

  63. Yoshida, R., Kiyozuka, Y., Ichiyoshi, H., et al. (1999). Change in telomerase activity during human colorectal carcinogenesis. Anticancer Res. 19, 2167–2172

    PubMed  CAS  Google Scholar 

  64. Bamberger, C.M., Else, T., Bamberger, A.M., et al. (1999). Telomerase activity in benign and malignant adrenal tumors. Exp. Clin. Endocrinol. Diabet. 107, 272–275.

    Article  CAS  Google Scholar 

  65. Arai, Y., Yajima, T., Yagihashi, A., et al. (2000). Limitations of urinary telomerase activity measurement in urothelial cancer. Clin. Chim. Acta. 296, 35–44.

    Article  PubMed  CAS  Google Scholar 

  66. Shroyer, K.R., Thompson, L.C., Enomoto, T., et al. (1998). Telomerase expression in normal epthelium, reactive atypia, squamous dysplasia and squamous cell carcinoma of the uterine cervix. Am. J. Clin. Pathol. 109, 153–162.

    PubMed  CAS  Google Scholar 

  67. Yokoyama, Y., Takahashi, Y., Shinohara, A., et al. (1998). Telomerase activity in the female reproductive tract and neoplasms. Gynecol. Oncol. 68, 145–149.

    Article  PubMed  CAS  Google Scholar 

  68. Mayfield, M.P., Shah, T., Flannigan, G.M., et al. (1998). Telomerase activity in malignant and benign bladder conditions. Int. J. Mol. Med. 1, 835–840.

    PubMed  CAS  Google Scholar 

  69. Kim, N.W. (1997). Clinical implications of telomerase in cancer. Eur. J. Cancer 33, 781–786.

    Article  PubMed  CAS  Google Scholar 

  70. Carey, L.A., Kim, N.W., Goodman, S., et al. (1999). Telomerase activity and prognosis in primary breast cancers. J. Clin. Oncol. 17, 3075–3081.

    PubMed  CAS  Google Scholar 

  71. Dunham, M.A., Neumann, A.A., Fasching, C.L., et al. (2000). Telomere maintenance by recombination in human cells. Nat. Genet. 26, 447–450.

    Article  PubMed  CAS  Google Scholar 

  72. Keith, W.N., Sarvesvaran, J., and Downey, M. (2002). Analysis of Telomerase RNA Gene Expression by in situ hybridization. In: Methods in Molecular Biology vol. 191, Telomeres and Telomerase (Double, J.A. and Thompson, M.J., eds.) Humana Press, Totowa, NJ, pp. 65.

    Chapter  Google Scholar 

  73. Wei, R. and Younes, M., (2002). Immunohistochemical detection of telomerase reverse transcriptase in colorectal adenocarcinoma and benign colonic mucosa. Human Pathol. 33, 693–696.

    Article  CAS  Google Scholar 

  74. Masutomi, K., Kaneko, S., Yasukawa, M., et al. (2002). Identification of serum anti-human telomerase reverse transcriptase (hTERT) auto-antibodies during progression to hepatocellular carcinoma. Oncogene 21, 5946–5950.

    Article  PubMed  CAS  Google Scholar 

  75. Kelland, L.R. (2001) Telomerase:Biology and phase I trials. THE LANCET Oncology 2, 95–101.

    Article  PubMed  CAS  Google Scholar 

  76. Hahn, W.C., Stewart, S.A., Brooks, M.W., et al. (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat. Med. 5, 1164–1170.

    Article  PubMed  CAS  Google Scholar 

  77. Zhang, L., Mar, V., Zhou, W., et al. (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev. 13, 2388–2399.

    Article  PubMed  CAS  Google Scholar 

  78. Neidle, S. and Parkinson, G. (2002). Telomere maintenance as a target for anticancer drug discovery. Nat. Rev. Drug Disc. 1, 383–393.

    Article  CAS  Google Scholar 

  79. Kondo, S., Kondo, Y., Li, G., et al. (1998) Targeted therapy of human malignant glioma in a mouse model by 2-5A antisense directed against telomerase RNA. Oncogene 16, 3323–3330.

    Article  PubMed  CAS  Google Scholar 

  80. Yokoyama, Y., Takahashi, Y., Shinohara, A., et al. (1998). Attenuation of telomerase activity by a hammerhead ribozyme targeting the template region of telomerase RNA in endometrial carcinoma cells. Cancer Res. 58, 5406–5410.

    PubMed  CAS  Google Scholar 

  81. Hamilton, S.E., Simmons, C.G., Kathiriya, I.S., et al. (1999). Cellular delivery of peptide nucleic acids and inhibition of human telomerase. Chem. Biol. 6, 343–351.

    Article  PubMed  CAS  Google Scholar 

  82. Zahler, A.M., Williamson, J.R., Cech, T.R., et al. (1991). Inhibition of telomerase by G-quartet DNA structures. Nature 350, 718–720.

    Article  PubMed  CAS  Google Scholar 

  83. Mergny, J.-L., Mailliet, P., Lavelle, F., et al. (1999). The development of telomerase inhibitors: the G-quartet approach. Anticancer Drug Des. 14, 327–339.

    PubMed  CAS  Google Scholar 

  84. Gowan, S.M., Heald, R., Stevens, M.F.G., et al. (2001) Potent Inhibition of Telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes. Mol. Pharmacol, 60, 981–988.

    PubMed  CAS  Google Scholar 

  85. Blackburn, E.H. (2000) Telomere states and cell fates. Nature 408, 53–56.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael C Bibby.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bibby, M.C. An introduction to telomeres and telomerase. Mol Biotechnol 24, 295–301 (2003). https://doi.org/10.1385/MB:24:3:295

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/MB:24:3:295

Index Entries

Navigation