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.

  • Progress
  • Published:

Telomere states and cell fates

Nature volume 408, pages 53–56 (2000)Cite this article

Abstract

Telomere length has frequently been used as a means to predict the future life of cells. But by itself it can be a poor indicator of ageing or cell viability. What, then, is the important property of a telomere? Here recent findings are integrated into a new, probabilistic view of the telomere to explain how and when it can signal not only its own fate but also that of a cell.

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

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: Telomere switching.
Figure 2: Stochastic uncapping of telomeres and cellular senescence kinetics.

Similar content being viewed by others

References

  1. 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  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. Counter, C. M. et al. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc. Natl Acad. Sci. USA 95, 14723–14728 ( 1998).

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  6. Counter, C. M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 ( 1992).

    Article  CAS  Google Scholar 

  7. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25– 34 (1997).

    Article  CAS  Google Scholar 

  8. Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  10. Harley, C. B. Human ageing and telomeres. Ciba Foundation Symp. 211 , 129–139 (1997).

    CAS  Google Scholar 

  11. Cristofalo, V. J., Allen, R. G., Pignolo, R. J., Martin, B. G. & Beck, J. C. Relationship between donor age and the replicative lifespan of human cells in culture: a reevaluation. Proc. Natl Acad. Sci. USA 95, 10614– 10619 (1998).

    Article  ADS  CAS  Google Scholar 

  12. Frenck, R. W. Jr, Blackburn, E. H. & Shannon, K. M. The rate of telomere sequence loss in human leukocytes varies with age. Proc. Natl Acad. Sci. USA 95, 5607–5610 (1998).

    Article  ADS  CAS  Google Scholar 

  13. Weng, N. P., Hathcock, K. S. & Hodes, R. J. Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. Immunity 9, 151–157 ( 1998).

    Article  CAS  Google Scholar 

  14. Bassham, S., Beam, A. & Shampay, J. Telomere variation in Xenopus laevis. Mol. Cell. Biol. 18, 269–275 (1998).

    Article  CAS  Google Scholar 

  15. Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114– 10118 (1992).

    Article  ADS  CAS  Google Scholar 

  16. 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 

  17. Roy, J., Fulton, T. B. & Blackburn, E. H. Specific telomerase RNA residues distant from the template are essential for telomerase function. Genes Dev. 12, 3286–3300 (1998).

    Article  CAS  Google Scholar 

  18. Blackburn, E. H. et al. in Cold Spring Harbor Symposia on Quantitative Biology: Biological Responses to DNA Damage (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, in the press).

  19. Zhu, J., Wang, H., Bishop, J. M. & Blackburn, E. H. Telomerase extends the lifespan of virus-transformed human cells without net telomere lengthening. Proc. Natl Acad. Sci. USA 96, 3723–3728 (1999).

    Article  ADS  CAS  Google Scholar 

  20. Yang, J. et al. Human endothelial cell life extension by telomerase expression. J. Biol. Chem. 274, 26141– 26148 (1999).

    Article  CAS  Google Scholar 

  21. Ducray, C., Pommier, J. P., Martins, L., Boussin, F. D. & Sabatier, L. Telomere dynamics, end-to-end fusions and telomerase activation during the human fibroblast immortalization process. Oncogene 18, 4211–4223 (1999).

    Article  CAS  Google Scholar 

  22. McEachern, M. J. & Blackburn, E. H. Cap-prevented recombination between terminal telomeric repeat arrays (telomere CPR) maintains telomeres in Kluyveromyces lactis lacking telomerase. Genes Dev. 10, 1822–1834 ( 1996).

    Article  CAS  Google Scholar 

  23. Gravel, S., Larrivée, M., Labrecque, P. & Wellinger, R. J. Yeast Ku as a regulator of chromosomal DNA end structure. Science 280, 741–744 ( 1998).

    Article  ADS  CAS  Google Scholar 

  24. Hsu, H. L., Gilley, D., Blackburn, E. H. & Chen, D. J. Ku is associated with the telomere in mammals. Proc. Natl Acad. Sci. USA 96, 12454–12458 (1999).

    Article  ADS  CAS  Google Scholar 

  25. Bertuch, A. & Lundblad, V. Telomeres and double-strand breaks: trying to make ends meet. Trends Cell Biol. 8, 339–342 (1998).

    Article  CAS  Google Scholar 

  26. Le, S., Moore, J. K., Haber, J. E. & Greider, C. W. RAD50 and RAD51 define two pathways that collaborate to maintain telomeres in the absence of telomerase. Genetics 152, 143–152 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ritchie, K. B., Mallory, J. C. & Petes, T. D. Interactions of TLC1 (which encodes the RNA subunit of telomerase), TEL1, and MEC1 in regulating telomere length in the yeast Saccharomyces cerevisiae. Mol. Cell. Biol. 19, 6065–6075 (1999).

    Article  CAS  Google Scholar 

  28. Ahmed, S. & Hodgkin, J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans. Nature 403, 159–164 ( 2000).

    Article  ADS  CAS  Google Scholar 

  29. Sprung, C. N., Bryan, T. M., Reddel, R. R. & Murnane, J. P. Normal telomere maintenance in immortal ataxia telangiectasia cell lines. Mutat. Res. 379, 177–184 (1997).

    Article  CAS  Google Scholar 

  30. d'Adda di Fagagna, F. et al. Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability. Nature Genet. 23, 76–80 (1999).

    Article  CAS  Google Scholar 

  31. Evans, S. K. & Lundblad, V. Est1 and Cdc13 as comediators of telomerase access. Science 286, 117– 120 (1999).

    Article  CAS  Google Scholar 

  32. McEachern, M. J. & Blackburn, E. H. Runaway telomere elongation caused by telomerase RNA gene mutations. Nature 376, 403–409 (1995).

    Article  ADS  CAS  Google Scholar 

  33. Marcand, S., Gilson, E. & Shore, D. A protein-counting mechanism for telomere length regulation in yeast. Science 275, 986– 990 (1997).

    Article  CAS  Google Scholar 

  34. van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998).

    Article  CAS  Google Scholar 

  35. Krauskopf, A. & Blackburn, E. H. Rap1 protein regulates telomere turnover in yeast. Proc. Natl Acad. Sci. USA 95, 12486–12491 (1998).

    Article  ADS  CAS  Google Scholar 

  36. Smith, C. D. & Blackburn, E. H. Uncapping and deregulation of telomeres lead to detrimental cellular consequences in yeast. J. Cell Biol. 145, 203–214 (1999).

    Article  CAS  Google Scholar 

  37. Jones, R. B., Whitney, R. G. & Smith, J. R. Intramitotic variation in proliferative potential: stochastic events in cellular aging. Mech. Age. Dev. 29, 143–149 (1985).

    Article  CAS  Google Scholar 

  38. Pontaen, J., Stein, W. D. & Shall, S. A quantitative analysis of the aging of human glial cells in culture. J. Cell. Phys. 117, 342–352 (1983).

    Article  Google Scholar 

  39. Holliday, R. Endless quest. BioEssays 18, 3– 5 (1983).

    Article  Google Scholar 

  40. Karatza, C., Stein, W. D. & Shall, S. Kinetics of in vitro ageing of mouse embryo fibroblasts. J. Cell Sci. 65, 163–175 (1984).

    CAS  PubMed  Google Scholar 

  41. Herrera, E., Samper, E. & Blasco, M. A. Telomere shortening in mTR-/- embryos is associated with failure to close the neural tube. EMBO J. 18, 1172–1181 (1999).

    Article  CAS  Google Scholar 

  42. Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569– 574 (1998).

    Article  ADS  CAS  Google Scholar 

  43. Kirschner, M., Gerhart, J. & Mitchison, T. Molecular “Vitalism”. Cell 100, 79–88 (2000).

    Article  CAS  Google Scholar 

  44. Li, B., Oestreich, S. & de Lange, T. Identification of human Rap1: Implications for telomere evolution. Cell 101, 471– 483 (2000).

    Article  CAS  Google Scholar 

  45. Blackburn, E. H. The telomere and telomerase: how do they interact? Mt Sinai J. Med. 66, 292–300 ( 1999).

    CAS  PubMed  Google Scholar 

  46. Krauskopf, A. & Blackburn, E. H. Control of telomere growth by interactions of RAP1 with the most distal telomeric repeats. Nature 383, 354–357 ( 1996).

    Article  ADS  CAS  Google Scholar 

  47. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321– 1325 (1999).

    Article  CAS  Google Scholar 

  48. Kondo, S. et al. Antisense telomerase treatment: induction of two distinct pathways, apoptosis and differentiation. FASEB J. 12, 801–811 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I thank C. Gross, I. Herskowitz, B. Panning and C. Smith for discussions and comments on the manuscript.

Author information

Authors and Affiliations

  1. Departments of Biochemistry and Microbiology, University of California San Francisco, San Francisco, 94143-0448 , California, USA

    Elizabeth H. Blackburn

Authors
  1. Elizabeth H. Blackburn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elizabeth H. Blackburn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Blackburn, E. Telomere states and cell fates. Nature 408, 53–56 (2000). https://doi.org/10.1038/35040500

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35040500

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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