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.

TIMELINE

Telomeres and telomerase: three decades of progress

Abstract

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Human telomeres are repetitive DNA sequences at the ends of linear chromosomes.
Fig. 2: Telomere and telomerase timeline.

References

  1. Greider, C. W. Telomeres. Curr. Opin. Cell Biol. 3, 444–451 (1991).

    CAS  PubMed  Article  Google Scholar 

  2. de Lange, T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 19, 2100–2110 (2005).

    PubMed  Article  CAS  Google Scholar 

  3. Maciejowski, J. & de Lange, T. Telomeres in cancer: tumour suppression and genome instability. Nat. Rev. Mol. Cell. Biol. 18, 175–186 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Shay, J. W. Role of telomeres and telomerase in aging and cancer. Cancer Discov. 6, 584–593 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Shay, J. W., Wright, W. E. & Werbin, H. Defining the molecular mechanisms of human cell immortalization. Biochim. Biophys. Acta 1072, 1–7 (1991).

    CAS  PubMed  Google Scholar 

  6. Hemann, M. T., Strong, M. A., Hao, L. Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001).

    CAS  PubMed  Article  Google Scholar 

  7. Zou, Y., Sfeir, A., Gryaznov, S. M., Shay, J. W. & Wright, W. E. Does a sentinel or a subset of short telomeres determine replicative senescence? Mol. Biol. Cell 15, 3709–3718 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Lai, T.-P., Wright, W. E. & Shay, J. W. Comparison of telomere length measurement methods. Phil. Trans. R. Soc. B 373, 20160451 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  9. Aubert, G., Hills, M. & Lansdorp, P. M. Telomere length measurement-caveats and a critical assessment of the available technologies and tools. Mutat. Res. 730, 59–67 (2012).

    CAS  PubMed  Article  Google Scholar 

  10. Lai, T.-P. et al. A method for measuring the distribution of the shortest telomeres in cells and tissues. Nat. Commun. 8, 1356 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. Bendix, L., Horn, P. B., Jensen, U. B., Rubelj, I. & Kolvraa, S. The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells. Aging Cell 9, 383–397 (2010).

    CAS  PubMed  Article  Google Scholar 

  12. Wright, W. E., Pereira-Smith, O. M. & Shay, J. W. Reversible cellular senescence: a two-stage model for the immortalization of normal human diploid fibroblasts. Mol. Cell. Biol. 9, 3088–3092 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wright, W. E. & Shay, J. W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Gerontol. 27, 383–389 (1992).

    CAS  PubMed  Article  Google Scholar 

  14. Bryan, T. M., Englezou, A., Dalla-Pozza, L., Dunham, M. A. & Reddel, R. R. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat. Med. 3, 1271–1274 (1997).

    CAS  PubMed  Article  Google Scholar 

  15. Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  17. Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996).

    CAS  PubMed  Article  Google Scholar 

  18. Ulaner, G. A., Hu, J. F., Vu, T. H., Giudice, L. C. & Hoffman, A. R. Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int. J. Cancer 91, 644–649 (2001).

    CAS  PubMed  Article  Google Scholar 

  19. Wong, M. S., Wright, W. E. & Shay, J. W. Alternative splicing regulation of telomerase: a new paradigm? Trends Genet. 30, 430–438 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nat. Rev. Genet. 8, 299–309 (2007).

    CAS  PubMed  Article  Google Scholar 

  21. Robin, J. D. et al. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 28, 2464–2476 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Kim, W. et al. Regulation of the human telomerase gene TERT by telomere position effect over long distance (TPE-OLD): implications for aging and cancer. PLOS Biol. 14, 2000016 (2016).

    Article  CAS  Google Scholar 

  23. Robin, J. D. & Magdinier, F. Physiological and pathological aging affects chromatin dynamics, structure and function at the nuclear edge. Front. Genet. 7, 153 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. Kim, W. & Shay, J. W. Long-range telomere regulation of gene expression: telomere looping and telomere position effect over long distances (TPE-OLD). Differentiation 99, 1–9 (2018).

    PubMed  Article  CAS  Google Scholar 

  25. Lou, Z. et al. Endogenous genes near telomeres regulated by telomere length in human cells. Aging 1, 608–621 (2009).

    CAS  PubMed  PubMed Central  Article  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).

    CAS  PubMed  Google Scholar 

  27. Nakamura, T. M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955–959 (1997).

    CAS  PubMed  Article  Google Scholar 

  28. Feng, J. et al. The RNA component of human telomerase. Science 269, 1236–1241 (1995).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  30. Holohan, B., Wright, W. E. & Shay, J. W. Impaired telomere maintenance spectrum disorders. J. Cell Biol. 205, 289–229 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Calado, R. T. & Young, N. S. Telomere diseases. N. Eng. J. Med. 361, 2353–2365 (2009).

    CAS  Google Scholar 

  32. Mender, I. et al. Telomerase-mediated strategy for overcoming non-small cell lung cancer targeted therapy and chemotherapy resistance. Neoplasia 20, 826–837 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Shay, J. W. & Wright, W. E. Telomerase therapeutics for cancer: challenges and new directions. Nat. Rev. Drug Discov. 5, 477–584 (2006).

    Article  CAS  Google Scholar 

  34. Shay, J. W. & Wright, W. E. Mechanism-based combination telomerase inhibition therapy. Cancer Cell 7, 1–2 (2005).

    CAS  PubMed  Article  Google Scholar 

  35. Herbert, B.-S. et al. Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc. Natl Acad. Sci. USA 96, 14276–14281 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. Mender, I., Gryaznov, S., Dikmen, Z. G., Wright, W. E. & Shay, J. W. Induction of telomere dysfunction mediated by the telomerase substrate precursor, 6-thio-2-deoxyguanosine. Cancer Discov. 5, 82–95 (2015).

    CAS  PubMed  Article  Google Scholar 

  37. Wood, A. M. et al. TRF2 and lamin A/C interact to facilitate the functional organization of chromosome ends. Nat. Commun. 5, 5467 (2014).

    PubMed  Article  Google Scholar 

  38. Robin, J. D. et al. SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy. Genome Res. 25, 1781–1790 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Wood, A. M., Laster, K., Rice, E. I. & Kosak, S. T. A beginning of the end: new insights into the functional organization of telomeres. Nucleus 6, 172–178 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Stadler, G. et al. Human disease and telomere position effect (TPE): The regulation of DUX4 expression in facioscapulohumeral muscular dystrophy (FSHD). Nat. Struct. Mol. Biol. 20, 671–678 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Morgan, T. H. Random segregation versus coupling in Mendelian inheritance. Science 34, 384 (1911).

    CAS  PubMed  Article  Google Scholar 

  42. Muller, H. J. The remaking of chromosomes. Collect. Net 8, 182–195 (1938).

    Google Scholar 

  43. Creighton, H. B. & McClintock, B. A correlation of cytological and genetical crossing-over in Zea mays. Proc. Natl Acad. Sci. USA 17, 492–497 (1931).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. McClintock, B. The stability of broken ends of chromosomes in Zea mays. Genetics 26, 234–282 (1941).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. McClintock, B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc. Natl Acad. Sci. USA 25, 405–416 (1939).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. McClintock, B. Profiles in science. Letter from Barbara McClintock to Elizabeth H. Blackburn. NIH https://profiles.nlm.nih.gov/ps/retrieve/ResourceMetadata/LLBBDW (1983).

  47. Weismann, A. Collected Essays Upon Heredity and Kindred Biological Problems (eds Poulton, E. B., Schönland, S. & Shipley, A. E.) (Clarendon Press, Oxford, 1889).

  48. Carrel, A. & Ebeling, A. H. Age and multiplication of fibroblasts. J. Exp. Med. 34, 599–606 (1921).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    CAS  PubMed  Article  Google Scholar 

  50. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    CAS  PubMed  Article  Google Scholar 

  51. Rubin, H. Telomerase and cellular lifespan: ending the debate? Nat. Biotechnol. 16, 396–397 (1998).

    CAS  PubMed  Article  Google Scholar 

  52. Shay, J. W. & Wright, W. E. Hayflick, his limit, and cellular ageing. Nat. Rev. Mol. Cell. Biol. 1, 72–76 (2000).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  54. Olovnikov, A. M. A theory of marginotomy. The incomplete copying of template margin in enzymatic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 41, 181–190 (1973).

    CAS  PubMed  Article  Google Scholar 

  55. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  59. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. Meyne, J., Ratliff, R. L. & Moyzis, R. K. Conservation of the human telomere sequence (TTAGGG)n among vertebrates. Proc. Natl Acad. Sci. USA 86, 7049–7053 (1989).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. Gomes, N. M. V. et al. The comparative biology of mammalian telomeres: ancestral states and functional transitions. Aging Cell 10, 761–768 (2011).

    CAS  PubMed  Article  Google Scholar 

  62. Klobutcher, L. A., Swanton, M. T., Donini, P. & Prescott, D. M. All gene-szied DNA molecules in four specific of hypotrich have the same terminal sequence and an unusual 3’ terminus. Proc. Natl Acad. Sci. USA 78, 3015–3019 (1981).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. Gottschling, D. E. & Zakian, V. A. Telomere proteins: specific recognition and protection of the natural termini of Oxytricha macronuclear DNA. Cell 47, 195–205 (1986).

    CAS  PubMed  Article  Google Scholar 

  64. Lin, J. J. & Zakian, V. A. The Saccharomyces CDC13 protein is a single-strand TG1-3 telomeric DNA-binding protein in vitro that affects telomere behavior in vivo. Proc. Natl Acad. Sci. USA 93, 13760–13765 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. Nugent, C. I., Hughes, T. R., Lue, N. F. & Lundblad, V. Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance. Science 274, 249–252 (1996).

    CAS  PubMed  Article  Google Scholar 

  66. Baumann, P. & Cech, T. R. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 292, 1171–1175 (2001).

    CAS  PubMed  Article  Google Scholar 

  67. Buchman, A. R., Kimmerly, W. J., Rine, J. & Kornberg, R. D. Two DNA-binding factors recognize specific sequences at silencers, upstream activating sequences, autonomously replicating sequences, and telomeres in Saccharomyces cerevisiae. Mol. Cell. Biol. 8, 210–225 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Conrad, M. N., Wright, J. H., Wolf, A. J. & Zakian, V. A. RAP1 protein interacts with yeast telomeres in vivo: overproduction alters telomere structure and decreases chromosome stability. Cell 63, 739–750 (1990).

    CAS  PubMed  Article  Google Scholar 

  69. Lustig, A. J., Kurtz, S. & Shore, D. Involvement of the silencer and UAS binding protein RAP1 in regulation of telomere length. Science 250, 549–553 (1990).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  71. Marcand, S., Wotton, D., Gilson, E. & Shore, D. Rap1p and telomere length regulation in yeast. Ciba Found. Symp. 211, 76–93; discussion 93–103 (1997).

    CAS  PubMed  Google Scholar 

  72. Chong, L. et al. A human telomeric protein. Science 270, 1663–1667 (1995).

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  74. Bilaud, T. et al. Telomeric localization of TRF2, a novel human telobox protein. Nat. Genet. 17, 236–239 (1997).

    CAS  PubMed  Article  Google Scholar 

  75. Broccoli, D., Smogorzewska, A., Chong, L. & de Lange, T. Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat. Genet. 17, 231–235 (1997).

    CAS  PubMed  Article  Google Scholar 

  76. Smogorzewska, A. et al. Control of human telomere length by TRF1 and TRF2. Mol. Cell. Biol. 20, 1659–1668 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  78. Kim, S. H., Kaminker, P. & Campisi, J. TIN2, a new regulator of telomere length in human cells. Nat. Genet. 23, 405–412 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. National Center for Biotechnology Information. ACD, shelterin complex subunit and telomerase recruitment factor [Homo sapiens (human)]. NCBI Gene https://www.ncbi.nlm.nih.gov/gene/65057 (2018).

  80. O’Connor, M. S., Safari, A., Xin, H., Liu, D. & Songyang, Z. A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc. Natl Acad. Sci. USA 103, 11874–11879 (2006).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  81. Griffith, J. D. et al. Mammalian telomeres end in a large duplex loop. Cell 97, 503–514 (1999).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  86. Lindsey, J., McGill, N. I., Lindsey, L. A., Green, D. K. & Cooke, H. J. In vivo loss of telomeric repeats with age in humans. Mutat. Res. 256, 45–48 (1991).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  88. 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).

    CAS  PubMed  Article  Google Scholar 

  89. 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).

    CAS  Article  PubMed  Google Scholar 

  90. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  92. Shippen-Lentz, D. & Blackburn, E. H. Telomere terminal transferase activity from Euplotes crassus adds large numbers of TTTTGGGG repeats onto telomeric primers. Mol. Cell. Biol. 9, 2761–2764 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zahler, A. M. & Prescott, D. M. Telomere terminal transferase activity in the hypotrichous ciliate Oxytricha nova and a model for replication of the ends of linear DNA molecules. Nucleic Acids Res. 16, 6953–6972 (1988).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Harrington, L. et al. A mammalian telomerase-associated protein. Science 275, 973–977 (1997).

    CAS  PubMed  Article  Google Scholar 

  95. Harrington, L. et al. Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev. 11, 3109–3115 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  97. Kilian, A. et al. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum. Mol. Genet. 6, 2011–2019 (1997).

    CAS  PubMed  Article  Google Scholar 

  98. Vaziri, H. & Benchimol, S. Reconstitution of telomerase activity in human cells leads to elongation of telomeres and extended replicative lifespan. Curr. Biol. 8, 279–282 (1998).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  100. Hiyama, E. et al. Correlating telomerase activity levels with human neuroblastoma outcomes. Nat. Med. 1, 249–257 (1995).

    CAS  PubMed  Article  Google Scholar 

  101. Morales, C. P. et al. Lack of cancer-associated changes in human fibroblasts after immortalization with telomerase. Nat. Genet. 21, 115–118 (1999).

    CAS  PubMed  Article  Google Scholar 

  102. Hiyama, K. et al. Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J. Immunol. 155, 3711–3715 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Cawthon, R. M. Telomere measurement by quantitative PCR. Nucleic Acids Res. 30, e47 (2002).

    PubMed  PubMed Central  Article  Google Scholar 

  105. Verhulst, S. et al. Commentary: The reliability of telomere length measurements. Int. J. Epidemiol. 44, 1683–1686 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  106. Eisenberg, D. T. Telomere length measurement validity: the coefficient of variation is invalid and cannot be used to compare quantitative polymerase chain reaction and Southern blot telomere length measurement techniques. Int. J. Epidemiol. 45, 1295–1298 (2016).

    PubMed  Google Scholar 

  107. Baird, D. M., Rowson, J., Wynford-Thomas, D. & Kipling, D. Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat. Genet. 33, 203–207 (2003).

    CAS  PubMed  Article  Google Scholar 

  108. Baird, D. M. New developments in telomere length analysis. Exp. Gerontol. 40, 363–336 (2005).

    CAS  PubMed  Article  Google Scholar 

  109. Baerlocher, G. M., Vulto, I., de Jong, G. & Lansdorp, P. M. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat. Protoc. 1, 2365–2376 (2006).

    CAS  PubMed  Article  Google Scholar 

  110. Rufer, N., Dragowska, W., Thornbury, G., Roosnek, E. & Lansdorp, P. M. Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat. Biotechnol. 16, 743–747 (1998).

    CAS  PubMed  Article  Google Scholar 

  111. Ludlow, A. T. et al. Quantitative telomerase enzyme activity determination using droplet digital PCR with single cell resolution. Nucleic Acids Res. 42, e104 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. Huang, E. et al. The maintenance of telomere length in CD28+ T cells during lymphocyte stimulation. Sci. Rep. 7, 6785 (2017).

    PubMed  Article  CAS  Google Scholar 

  113. Opresko, P. L. & Shay, J. W. Telomere-associated aging disorders. Ageing Res. Rev. 33, 52–66 (2016).

    PubMed  Article  CAS  Google Scholar 

  114. Shay, J. W. & Wright, W. E. Telomeres in dyskeratosis congenita. Nat. Genet. 36, 437–438 (2004).

    CAS  PubMed  Article  Google Scholar 

  115. Garcia, C. K., Wright, W. E. & Shay, J. W. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 35, 7406–7416 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Armanios, M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J. Clin. Invest. 123, 996–1002 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Armanios, M. & Blackburn, E. H. The telomere syndromes. Nat. Rev. Genet. 13, 693–704 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Chojnowski, A. et al. Progerin reduces LAP2α-telomere association in Hutchinson–Gilford progeria. eLife 4, e07759 (2015).

    PubMed Central  Article  Google Scholar 

  119. Cao, K. et al. Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. J. Clin. Invest. 121, 2833–2844 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Gordon, L. B., Rothman, F. G., López-Otín, C. & Misteli, T. Progeria: a paradigm for translational medicine. Cell 156, 400–407 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Dorado, B. & Andres, V. A-type lamins and cardiovascular disease in premature aging syndromes. Curr. Opin. Cell Biol. 46, 17–25 (2017).

    CAS  PubMed  Article  Google Scholar 

  122. van Steensel, B. & Belmont, A. S. Lamina-associated domains: links with chromosome architecture, heterochromatin, and gene repression. Cell 169, 780–791 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. McCord, R. P. et al. Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson–Gilford progeria syndrome. Genome Res. 23, 260–269 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  125. 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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  126. Shay, J. W. & Wright, W. E. Mutant dyskerin ends relationship with telomerase. Science 286, 2284–2285 (1999).

    CAS  PubMed  Article  Google Scholar 

  127. Heiss, N. S. et al. X-Linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat. Genet. 19, 32–38 (1998).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  129. Keller, R. B. et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr. Blood Cancer. 59, 311–314 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  130. Kirwan, M. & Dokal, I. Dyskeratosis congenita: a genetic disorder of many faces. Clin. Genet. 73, 103–112 (2008).

    CAS  PubMed  Article  Google Scholar 

  131. Kirwan, M. et al. Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia. Hum. Mutat. 30, 1567–1573 (2009).

    CAS  PubMed  Article  Google Scholar 

  132. Sasa, G. S., Ribes-Zamora, A., Nelson, N. D. & Bertuch, A. A. Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clin. Genet. 81, 470–478 (2012).

    CAS  PubMed  Article  Google Scholar 

  133. Savage, S. A. et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am. J. Hum. Genet. 82, 501–509 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Gramatges, M. M. & Bertuch, A. A. Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy. Transl Res. 162, 353–363 (2013).

    CAS  PubMed  Article  Google Scholar 

  135. Fogarty, P. F. et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 362, 1628–1630 (2003).

    CAS  PubMed  Article  Google Scholar 

  136. Gadalla, S. M., Cawthon, R., Giri, N., Alter, B. P. & Savage, S. A. Telomere length in blood, buccal cells, and fibroblasts from patients with inherited bone marrow failure syndromes. Aging 2, 867–874 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  137. Goldman, F. R. et al. The effect of TERC haploinsufficiency on the inheritance of telomere length. Proc. Natl Acad. Sci. USA 102, 17119–17124 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  138. Parry, E. M., Alder, J. K., Qi, X., Chen, J. J. & Armanios, M. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 117, 5607–5611 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Young, N. S. Bone marrow failure and the new telomere diseases: practice and research. Hematology 17 (Suppl. 1), 18–21 (2012).

    CAS  PubMed  Article  Google Scholar 

  140. Polvi, A. T. et al. Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. Am. J. Hum. Genet. 90, 540–549 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Trahan, C. & Dragon, F. Dyskeratosis congenita mutations in the H/ACA domain of blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol. Dis. 27, 353–357 (2009).

    Google Scholar 

  142. Tsakiri, K. D. et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc. Natl Acad. Sci. USA 104, 7552–7557 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  143. Armanios, M. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).

    CAS  PubMed  Article  Google Scholar 

  144. Armanios, M. Telomerase and idiopathic pulmonary fibrosis. Mutat. Res. 730, 52–58 (2012).

    CAS  PubMed  Article  Google Scholar 

  145. Cronkhite, J. T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Diaz de Leon, A. et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLOS ONE 5, e10680 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. Tsangaris, E. et al. Ataxia and pancytopenia caused by a mutation in TINF2. Hum. Genet. 124, 507–513 (2008).

    CAS  PubMed  Article  Google Scholar 

  148. Vulliamy, T., Marrone, A., Dokal, I. & Mason, P. J. Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359, 2168–2170 (2002).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  150. Calado, R. T. et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc. Natl Acad. Sci. USA 106, 1187–1192 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. Touzot, F. et al. Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc. Natl Acad. Sci. USA 107, 10097–10102 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. Holohan, B. et al. Impaired telomere maintenance in Alazami syndrome patients with LARP7 deficiency. BMC Genomics 17 (Suppl. 9), 80–87 (2016).

    Google Scholar 

  153. Dekker, J. & Mirny, L. The 3D genome as moderator of chromosomal communication. Cell 164, 1110–1120 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Chandra, T. & Kirschner, K. Chromosome organization during ageing and senescence. Curr. Opin. Cell Biol. 40, 161–167 (2016).

    CAS  PubMed  Article  Google Scholar 

  155. Rowley, M. J. & Corces, V. G. The three-dimensional genome: principles and roles of long-distance interactions. Curr. Opin. Cell. Biol. 40, 8–14 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. Canela, A. et al. Genome organization drives chromosome fragility. Cell 170, 507–521 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Gottschling, D. E., Aparicio, O. M., Billinton, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751–762 (1990).

    CAS  PubMed  Article  Google Scholar 

  158. Kulkarni, A., Zschenker, O., Reynolds, G., Miller, D. & Murnane, J. P. Effect of telomere proximity on telomere position effect, chromosome healing, and sensitivity to DNA double-strand breaks in a human tumor cell line. Mol. Cell. Biol. 30, 578–589 (2010).

    CAS  PubMed  Article  Google Scholar 

  159. Baur, J. A., Zou, Y., Shay, J. W. & Wright, W. E. Telomere position effect in human cells. Science 292, 2075–2077 (2001).

    CAS  PubMed  Article  Google Scholar 

  160. Bolzan, A. D. Interstitial telomeric sequences in vertebrate chromosomes: Origin, function, instability, and evolution. Mutat. Res. 773, 51–65 (2017).

    CAS  Article  Google Scholar 

  161. Burla, R., La Torre, M. & Saggio, I. Mammalian telomeres and their partnership with lamins. Nucleus 7, 187–202 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Simonet, T. et al. The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Res. 21, 1028–1038 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (2001).

    Article  Google Scholar 

  164. Rose, R. & Charlesworth, B. A test of evolutionary theories of senescence. Nature 287, 141–142 (1980).

    CAS  PubMed  Article  Google Scholar 

  165. Partridge, L. Evolutionary theories of ageing applied to long-lived organisms. Exp. Gerontol. 36, 641–650 (2001).

    CAS  PubMed  Article  Google Scholar 

  166. Williams, P. D. & Day, T. Antagonists pleiotropy, mortality source interactions, and the evolutionary theory of senescence. Evolution 57, 1478–1488 (2003).

    PubMed  Article  Google Scholar 

  167. Shay, J. W. Telomeres and aging. Curr. Opin. Cell Biol. 52, 1–7 (2018).

    CAS  PubMed  Article  Google Scholar 

  168. Luke, B. & Lingner, J. TERRA: telomere repeat-containing RNA. EMBO J. 28, 2503–2510 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  170. Gillis, A. J., Schuller, A. P. & Skordalakes, E. Structure of the Tribolium castaneum telomerase catalytic subunit. Nature 455, 633–637 (2008).

    CAS  PubMed  Article  Google Scholar 

  171. Horn, S. et al. TERT promoter mutations in familial and sporadic melanoma. Science 339, 959–961 (2013).

    CAS  PubMed  Article  Google Scholar 

  172. Huang, F. W. et al. Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957–959 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Sandin, S. & Rhodes, D. Telomerase structure. Curr. Opin. Struct. Biol. 25, 104–110 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Nguyen, T. H. D. et al. Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nature 557, 190–196 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Jiang, J. et al. Structure of telomerase with telomeric DNA. Cell 173, 1179–1190 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  176. Sarek, G., Vannier, J. B., Panier, S., Petrini, J. H. & Boulton, S. J. TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding. Mol. Cell 57, 622–635 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. Walne, A. J., T. Vulliamy, T., Kirwan, M., Plagnol, V. & Dokal, I. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am. J. Hum. Genet. 92, 448–453 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. Vannier, J. B. J. B., Pavicic-Kaltenbrunner, V., Petalcorin, M. I., Ding, H. & Boulton, S. J. RTEL1 dismantles T Loops and counteracts telomeric G4-DNA to maintain telomere integrity. Cell 149, 795–806 (2012).

    CAS  PubMed  Article  Google Scholar 

  179. Ding, H. et al. Regulation of murine telomere length by Rtel: an essential gene encoding a helicase-like protein. Cell 117, 873–886 (2004).

    CAS  PubMed  Article  Google Scholar 

  180. Ballew, B. J. et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum. Genet. 132, 473–480 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. Ballew, B. J. et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLOS Genet. 9, e1003695 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. Zhong, F. et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 25, 11–16 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. Stuart, B. D. et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat. Genet. 47, 512–517 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. Burris, A. M. et al. Hoyeraal-Hreidarsson Syndrome due to PARN mutations: fourteen years of follow-up. Pediatr. Neurol. 56, 62–68 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  185. Vulliamy, T. et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc. Natl Acad. Sci. USA 105, 8073–8078 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  186. Walne, A. J. et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Mol. Genet. 16, 1619–1629 (2007).

    CAS  PubMed  Article  Google Scholar 

  187. Metcalfe, A. et al. Accelerated telomere shortening in ataxia telangiectasia. Nat. Genet. 13, 350–353 (1996).

    CAS  PubMed  Article  Google Scholar 

  188. Smilenov, L. B. et al. Influence of ATM function on telomere metabolism. Oncogene 15, 2659–2665 (1997).

    CAS  PubMed  Article  Google Scholar 

  189. Wood, L. D. et al. Characterization of ataxia telangiectasia fibroblasts with extended life-span through telomerase expression. Oncogene 20, 278–288 (2001).

    CAS  PubMed  Article  Google Scholar 

  190. Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003).

    CAS  PubMed  Article  Google Scholar 

  191. Zimmermann, M. M., Kibe, T., Kabir, S. & de Lange, T. TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling. Genes Dev. 28, 2477–2491 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  192. Du, X. et al. Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genes. Mol. Cell. Biol. 24, 8437–8446 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. Kellermayer, R. The versatile RECQL4. Genet. Med. 8, 213–216 (2006).

    CAS  PubMed  Article  Google Scholar 

  194. Van Maldergem, L. et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J. Med. Genet. 43, 148–152 (2006).

    PubMed  Article  CAS  Google Scholar 

  195. Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nat. Genet. 36, 877–882 (2004).

    CAS  PubMed  Article  Google Scholar 

  196. Crabbe, L. L., Jauch, A., Naeger, C. M., Holtgreve-Grez, H. & Karlseder, J. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc. Natl Acad. Sci. USA 104, 2205–2210 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  197. Crabbe, L. L., Verdun, R. E., Haggblom, C. I. & Karlseder, J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306, 1951–1953 (2004).

    CAS  Article  PubMed  Google Scholar 

  198. Opresko, P. L. et al. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14, 763–774 (2004).

    CAS  PubMed  Article  Google Scholar 

  199. Edwards, D. N., Orren, D. K. & Machwe, A. Strand exchange of telomeric DNA catalyzed by the Werner syndrome protein (WRN) is specifically stimulated by TRF2. Nucleic Acids Res. 42, 7748–7761 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. Romero, D. P. & Blackburn, E. H. A conserved secondary structure for telomerase RNA. Cell 67, 343–353 (1991).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health (NIH) (AG01228), the Harold Simmons National Cancer Institute Designated Comprehensive Cancer Center support grant (CA142543) and the Southland Financial Corporation Distinguished Chair in Geriatric Research. This work was performed in laboratories constructed with support from the NIH (C06 RR30414). Owing to limited space, the authors apologize for not including all the advances in this field.

Author information

Authors and Affiliations

Authors

Contributions

J.W.S. researched content for the article. Both authors contributed to discussing the content, writing, reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Jerry W. Shay.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Jerry W. Shay and Woodring Wright’s homepage: http://www4.utsouthwestern.edu/cellbio/shay-wright/index.html

Telomerase Database: http://telomerase.asu.edu/

Glossary

Alternative lengthening of telomeres

(ALT). A telomerase-independent mechanism of maintaining telomere length that involves DNA recombination events.

Chromosome

The thread-like structure in the nucleus that carries genetic information. A normal human cell has 23 pairs of chromosomes (46 total chromosomes). Twenty-two pairs are called somatic or body chromosomes. The remaining two chromosomes are called sex chromosomes and determine whether a person is a male or a female.

Genetic anticipation

A genetic disorder that is passed on to the next generation with an earlier age of disease and an increase in severity of disease. In the telomere field, this can be due to germline transmission of shorter telomeres in succeeding generations.

Hayflick limit

The inability of cells to divide (replicate) indefinitely in culture.

Senescence

The process of cellular ageing generally thought to be irreversible. Senescence can be initiated by short telomeres and by genotoxic stressors (in an occurrence often termed premature senescence).

Shelterin

A six-member protein complex associated with telomeric DNA that protects the telomeres from being recognized as damaged DNA needing repair.

Telomerase

The ribonucleoprotein enzyme complex that adds telomeric sequences to telomeres and has been associated with cellular immortality.

Telomeres

The long natural end sequences of a chromosome composed of repetitive DNA sequences (such as hexameric, TTAGGGn repeats in mammals).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shay, J.W., Wright, W.E. Telomeres and telomerase: three decades of progress. Nat Rev Genet 20, 299–309 (2019). https://doi.org/10.1038/s41576-019-0099-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41576-019-0099-1

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer