Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging

Nature Medicine volume 12, pages 1133–1138 (2006)Cite this article

The telomere problem

Scientific discoveries are each individual and occur by their own unique path. However, there are key ingredients that set the stage for them. Many of these ingredients were important in the discovery of telomerase: talking with scientists from different fields, paying attention to unusual findings and taking the risks of doing crazy experiments. We will describe how a combination of these ingredients and productive collaborations led us to postulate and discover telomerase.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Yeast sequences are added to Tetrahymena telomeres in vivo.
Figure 2: Tetrahymena sequences are added to yeast telomeres in vitro.

Reprinted from Greider, C.W. & Blackburn, E.H. Cell 43, 405–413 (1985).

Figure 3: Cumulative citations for telomerase in Medline.

References

  1. McClintock, B. Cytological observations of deficiencies involving known genes, translocations and an inversion in Zea mays. Missouri Agr. Exp. Sta. Res. Bull. 163, 1–48 (1931).

    Google Scholar 

  2. Muller, H.J. The remaking of chromosomes. Collecting Net 13, 181–198 (1938).

    Google Scholar 

  3. Watson, J.D. & Crick, F.H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171, 737–738 (1953).

    Article  CAS  Google Scholar 

  4. Kornberg, A. DNA Synthesis (W.H. Freeman, San Francisco, 1974).

    Google Scholar 

  5. Watson, J.D. Origin of concatameric T7 DNA. Nat. New Biol. 239, 197–201 (1972).

    Article  CAS  Google Scholar 

  6. Blackburn, E.H. & Szostak, J.W. The molecular structure of centromeres and telomeres. Annu. Rev. Biochem. 53, 163–194 (1984).

    Article  CAS  Google Scholar 

  7. Wu, R. & Taylor, E. Nucleotide sequence analysis of DNA. II. Complete nucleotide sequence of the cohesive ends of bacteriophage lambda DNA. J. Mol. Biol. 57, 491–511 (1971).

    Article  CAS  Google Scholar 

  8. Blackburn, E.H. & Gall, J.G. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 120, 33–53 (1978).

    Article  CAS  Google Scholar 

  9. Yao, M.C., Blackburn, E. & Gall, J.G. Amplification of the rRNA genes in Tetrahymena. Cold Spring Harb. Symp. Quant. Biol. 43, 1293–1296 (1979).

    Article  CAS  Google Scholar 

  10. Yao, M.C., Blackburn, E. & Gall, J. Tandemly repeated C-C-C-C-A-A hexanucleotide of Tetrahymena rDNA is present elsewhere in the genome and may be related to the alteration of the somatic genome. J. Cell Biol. 90, 515–520 (1981).

    Article  CAS  Google Scholar 

  11. Johnson, E.M. A family of inverted repeat sequences and specific single-strand gaps at the termini of the Physarum rDNA palindrome. Cell 22, 875–886 (1980).

    Article  CAS  Google Scholar 

  12. Emery, H.S. & Weiner, A.M. An irregular satellite sequence is found at the termini of the linear extrachromosomal rDNA in Dictyostelium discoideum. Cell 26, 411–419 (1981).

    Article  CAS  Google Scholar 

  13. Blackburn, E.H. et al. DNA termini in ciliate macronuclei. Cold Spring Harb. Symp. Quant. Biol. 47, 1195–1207 (1983).

    Article  Google Scholar 

  14. Pan, W.C. & Blackburn, E.H. Single extrachromosomal ribosomal RNA gene copies are synthesized during amplification of the rDNA in Tetrahymena. Cell 23, 459–466 (1981).

    Article  CAS  Google Scholar 

  15. Katzen, A.L., Cann, G.M. & Blackburn, E.H. Sequence-specific fragmentation of macronuclear DNA in a holotrichous ciliate. Cell 24, 313–320 (1981).

    Article  CAS  Google Scholar 

  16. Klobutcher, L.A., Swanton, M.T., Donini, P. & Prescott, D.M. All gene-sized DNA molecules in four species of hypotrichs have the same terminal sequence and an unusual 3′ terminus. Proc. Natl. Acad. Sci. USA 78, 3015–3019 (1981).

    Article  CAS  Google Scholar 

  17. Boswell, R.E., Klobutcher, L.A. & Prescott, D.M. Inverted terminal repeats are added to genes during macronuclear development in Oxytricha nova. Proc. Natl. Acad. Sci. USA 79, 3255–3259 (1982).

    Article  CAS  Google Scholar 

  18. Orr-Weaver, T.L., Szostak, J.W. & Rothstein, R.J. Yeast transformation: a model system for the study of recombination. Proc. Natl. Acad. Sci. USA 78, 6354–6358 (1981).

    Article  CAS  Google Scholar 

  19. Szostak, J.W. & Blackburn, E.H. Cloning yeast telomeres on linear plasmid vectors. Cell 29, 245–255 (1982).

    Article  CAS  Google Scholar 

  20. Shampay, J., Szostak, J.W. & Blackburn, E.H. DNA sequences of telomeres maintained in yeast. Nature 310, 154–157 (1984).

    Article  CAS  Google Scholar 

  21. Murray, A.W. & Szostak, J.W. Construction of artificial chromosomes in yeast. Nature 305, 189–193 (1983).

    Article  CAS  Google Scholar 

  22. Murray, A.W., Schultes, N.P. & Szostak, J.W. Chromosome length controls mitotic chromosome segregation in yeast. Cell 45, 529–536 (1986).

    Article  CAS  Google Scholar 

  23. Dawson, D.S., Murray, A.W. & Szostak, J.W. An alternative pathway for meiotic chromosome segregation in yeast. Science 234, 713–717 (1986).

    Article  CAS  Google Scholar 

  24. Bernards, A., Michels, P.A., Lincke, C.R. & Borst, P. Growth of chromosomal ends in multiplying trypanosomes. Nature 303, 592–597 (1983).

    Article  CAS  Google Scholar 

  25. Walmsley, R.W., Chan, C.S., Tye, B.-K. & Petes, T.D. Unusual DNA sequences associated with the ends of yeast chromosomes. Nature 310, 157–160 (1984).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Greider, C.W. & Blackburn, E.H. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51, 887–898 (1987).

    Article  CAS  Google Scholar 

  28. Greider, C.W. & Blackburn, E.H. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337, 331–337 (1989).

    Article  CAS  Google Scholar 

  29. Yu, G.-L., Bradley, J.D., Attardi, L.D. & Blackburn, E.H. In vivo alteration of telomere sequences and senescence caused by mutated Tetrahymena telomerase RNAs. Nature 344, 126–132 (1990).

    Article  CAS  Google Scholar 

  30. Lundblad, V. & Szostak, J.W. A mutant with a defect in telomere elongation leads to senescence in yeast. Cell 57, 633–643 (1989).

    Article  CAS  Google Scholar 

  31. Cohn, M. & Blackburn, E.H. Telomerase in yeast. Science 269, 396–400 (1995).

    Article  CAS  Google Scholar 

  32. Prescott, J. & Blackburn, E.H. Telomerase RNA mutations in Saccharomyces cerevisiae alter telomerase action and reveal nonprocessivity in vivo and in vitro. Genes Dev. 11, 528–540 (1997).

    Article  CAS  Google Scholar 

  33. Lingner, J., Cech, T.R., Hughes, T.R. & Lundblad, V. Three Ever Shorter Telomere (EST) genes are dispensable for in vitro yeast telomerase activity. Proc. Natl. Acad. Sci. USA 94, 11190–11195 (1997).

    Article  CAS  Google Scholar 

  34. Nugent, C.I. & Lundblad, V. The telomerase reverse transcriptase: components and regulation. Genes Dev. 12, 1073–1085 (1998).

    Article  CAS  Google Scholar 

  35. Lendvay, T.S., Morris, D.K., Sah, J., Balasubramanian, B. & Lundblad, V. Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics 144, 1399–1412 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lingner, J. et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567 (1997).

    Article  CAS  Google Scholar 

  37. Cooke, H.J., Brown, W.R. & Rappold, G.A. Hypervariable telomeric sequences from the human sex chromosomes are pseudoautosomal. Nature 317, 687–692 (1985).

    Article  CAS  Google Scholar 

  38. Moyzis, R.K. et al. A highly conserved repetitive DNA sequence (TTAGGG)n, present at the telomeres of human chromosomes. Proc. Natl. Acad. Sci. USA 85, 6622–6626 (1988).

    Article  CAS  Google Scholar 

  39. Allshire, R.C. et al. Telomeric repeats from T. thermophila cross hybridize with human telomeres. Nature 332, 656–659 (1988).

    Article  CAS  Google Scholar 

  40. Morin, G.B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521–529 (1989).

    Article  CAS  Google Scholar 

  41. Olovnikov, A.M. A theory of marginotomy. J. Theor. Biol. 41, 181–190 (1973).

    Article  CAS  Google Scholar 

  42. Harley, C.B., Futcher, A.B. & Greider, C.W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    Article  CAS  Google Scholar 

  43. Bodnar, A.G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. de Lange, T. et al. Structure and variability of human chromosome ends. Mol. Cell. Biol. 10, 518–527 (1990).

    Article  CAS  Google Scholar 

  46. Kim, N.W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2014 (1994).

    Article  CAS  Google Scholar 

  47. de Lange, T. & Jacks, T. For better or worse? Telomerase inhibition and cancer. Cell 98, 273–275 (1999).

    Article  CAS  Google Scholar 

  48. Hackett, J.A. & Greider, C.W. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis. Oncogene 21, 619–626 (2002).

    Article  CAS  Google Scholar 

  49. Chen, J.L., Blasco, M.A. & Greider, C.W. Secondary structure of vertebrate telomerase RNA. Cell 100, 503–514 (2000).

    Article  CAS  Google Scholar 

  50. Mitchell, J.R., Cheng, J. & Collins, K. A box H/ACA small nucleolar RNA-like domain at the human telomerase RNA 3′ end. Mol. Cell. Biol. 19, 567–576 (1999).

    Article  CAS  Google Scholar 

  51. Ruggero, D. et al. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science 299, 259–262 (2003).

    Article  CAS  Google Scholar 

  52. Mitchell, J.R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).

    Article  CAS  Google Scholar 

  53. Chen, J.L. & Greider, C.W. Telomerase RNA structure and function: implications for dyskeratosis congenita. Trends Biochem. Sci. 29, 183–192 (2004).

    Article  CAS  Google Scholar 

  54. Vulliamy, T. et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001).

    Article  CAS  Google Scholar 

  55. Vulliamy, T. et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat. Genet. 36, 447–449 (2004).

    Article  CAS  Google Scholar 

  56. Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005).

    Article  CAS  Google Scholar 

  57. Armanios, M. et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Natl. Acad. Sci. USA 102, 15960–15964 (2005).

    Article  CAS  Google Scholar 

  58. Hao, L.Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of California, San Francisco, 600 16th Street, MC 2200, San Francisco, 94158-2517, California, USA

    Elizabeth H Blackburn

  2. Daniel Nathans Professor and Director, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 603 PCTB, 725 North Wolfe Street, Baltimore, 21205, Maryland, USA

    Carol W Greider

  3. Professor of Genetics at Department of Molecular Biology and Center for Computational and Integrative Biology, Harvard Medical School, Simches Research Center, 85 Cambridge Street, Boston, 02114, Massachusetts, USA

    Jack W Szostak

Authors
  1. Elizabeth H Blackburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carol W Greider
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jack W Szostak
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blackburn, E., Greider, C. & Szostak, J. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12, 1133–1138 (2006). https://doi.org/10.1038/nm1006-1133

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1006-1133

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing