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  • Review Article
  • Published:

Telomeres and human disease: ageing, cancer and beyond

Nature Reviews Genetics volume 6, pages 611–622 (2005)Cite this article

Key Points

  • Telomeres are specialized chromatin structures at the ends of chromosomes, which consist of tandem DNA repeats (of TTAGGG) and associated proteins. Telomeres are also bound by nucleosome arrays, which contain epigenetic modifications that are characteristic of constitutive heterochromatin.

  • Telomeres protect chromosome ends from repair and degradation activities. This function is impaired by both the shortening of TTAGGG repeats to below a critical length, and the loss of telomere-binding proteins.

  • Dysfunctional telomeres trigger a DNA damage response, which results in cell-cycle arrest or apoptosis. Telomere dysfunction can also lead to end-to-end chromosome fusions, and can interfere with the repair of DNA lesions in non-telomeric regions, resulting in hypersensitivity to various genotoxic agents.

  • Telomerase is a cellular reverse transcriptase that synthesizes de novo telomeric repeats at chromosome ends. Most somatic tissues lack telomerase activity and show progressive telomere shortening coupled to cell division.

  • Various diseases associated with ageing, including cancer, as well as a number of premature ageing syndromes, are characterized by critically short telomeres. Telomere shortening and the absence of telomerase in normal tissues is a tumour-suppression mechanism. By contrast, tumours aberrantly upregulate telomerase, which elongates short telomeres and allows continuous growth.

  • Mice that lack telomerase activity age prematurely and are more resistant to cancer. Human premature ageing syndromes that are characterized by short telomeres are recapitulated in the mouse only when in the context of telomerase-deficiency and short telomeres.

  • The telomerase core components telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), as well as telomerase-interacting protein dyskeratosis congenita 1, dyskerin (DKC1), are mutated in the premature ageing human diseases dyskeratosis congenita and aplastic anaemia.

  • Several telomere-binding proteins are altered in human cancer and premature ageing syndromes that are characterized by chromosomal instability.

  • Telomerase and telomere-binding proteins are new potential targets for anti-cancer and anti-ageing therapies.

Abstract

Telomere length and telomerase activity are important factors in the pathobiology of human disease. Age-related diseases and premature ageing syndromes are characterized by short telomeres, which can compromise cell viability, whereas tumour cells can prevent telomere loss by aberrantly upregulating telomerase. Altered functioning of both telomerase and telomere-interacting proteins is present in some human premature ageing syndromes and in cancer, and recent findings indicate that alterations that affect telomeres at the level of chromatin structure might also have a role in human disease. These findings have inspired a number of potential therapeutic strategies that are based on telomerase and telomeres.

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Figure 1: Telomere structure and telomerase activity.
Figure 2: Epigenetic regulation of telomeric chromatin and implications for disease.
Figure 3: Telomerase and telomere length in tumorigenesis.

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References

  1. De Lange, T. Protection of mammalian telomeres. Oncogene 21, 532–540 (2002).

    CAS  PubMed  Google Scholar 

  2. Blackburn, E. H. Switching and signaling at the telomere. Cell 106, 661–673 (2001).

    CAS  PubMed  Google Scholar 

  3. Collins, K. & Mitchell, J. R. Telomerase in the human organism. Oncogene 21, 564–579 (2002).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Nikitina, T. & Woodcock, C. L. Chromatin loops at the ends of chromosomes. J. Cell Biol. 166, 161–165 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. De Lange, T. T-loops and the origin of telomeres. Nature Rev. Mol. Cell Biol. 5, 323–329 (2004). A must-read review on the origins of telomeres and the formation of telomeric loops (T loops). A clear connection between T-loop formation and homologous recombination mechanisms is proposed.

    CAS  Google Scholar 

  7. Tommerup, H., Dousmanis, A. & de Lange, T. Unusual chromatin in human telomeres. Mol. Cell. Biol. 14, 5777–5785 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Garcia Cao, M. et al. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nature Genet. 36, 94–99 (2004). This paper showed that mammalian telomeres contain the main marks of constitutive heterochromatin and that epigenetic modifications represent a higher-order telomere-length control mechanism in mammals.

    CAS  PubMed  Google Scholar 

  9. Gonzalo, S. et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nature Cell Biol. 7, 420–428 (2005).

    CAS  PubMed  Google Scholar 

  10. Peters, A. H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    CAS  PubMed  Google Scholar 

  11. Schotta, G. et al. A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 8, 1251–1262 (2004).

    Google Scholar 

  12. Garcia-Cao, M., Gonzalo, S., Dean, D. & Blasco, M. A. A role for the Rb family of proteins in controlling telomere length. Nature Genet. 32, 415–419 (2002).

    CAS  PubMed  Google Scholar 

  13. Perrod, S. & Gasser, S. M. Long-range silencing and position effects at telomeres and centromeres: parallels and differences. Cell. Mol. Life Sci. 60, 2303–2318 (2003).

    CAS  PubMed  Google Scholar 

  14. Baur, J. A., Zou, Y., Shay, J. W. & Wright, W. E. Telomere position effect in human cells. Science 292, 2075–2077 (2001). The authors provide conclusive evidence that telomere position effect (the silencing of genes near the telomeres) operates in mammalian cells.

    CAS  PubMed  Google Scholar 

  15. Koering, C. E. et al. Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep. 3, 1055–1061 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Shiels, P. G. et al. Analysis of telomere lengths in cloned sheep. Nature 399, 316–317 (1999).

    CAS  PubMed  Google Scholar 

  17. Lanza, R. P. et al. Extension of cell life-span and telomere length in animals cloned from senescent somatic cells. Science 288, 665–669 (2000).

    CAS  PubMed  Google Scholar 

  18. Ahmad, K. & Henikoff, S. Epigenetic consequences of nucleosome dynamics. Cell 111, 281–284 (2002).

    CAS  PubMed  Google Scholar 

  19. Smogorzewska, A. & de Lange, T. Regulation of telomerase by telomeric proteins. Annu. Rev. Biochem. 73, 177–208 (2004).

    CAS  PubMed  Google Scholar 

  20. Karlseder, J. et al. Targeted deletion reveals an essential function for the telomere length regulator Trf1. Mol. Cell. Biol. 23, 6533–6541 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Dynek, J. N. & Smith, S. Resolution of sister telomere association is required for progression through mitosis. Science 304, 97–100 (2004). This paper provides evidence for the role of telomere-binding proteins in sister chromatid cohesion, therefore linking telomere function with cell division.

    CAS  PubMed  Google Scholar 

  22. Chiang, Y. J., Kim, S. H., Tessarollo, L., Campisi, J. & Hodes, R. J. Telomere-associated protein TIN2 is essential for early embryonic development through a telomerase-independent pathway. Mol. Cell. Biol. 15, 6631–6634 (2004).

    Google Scholar 

  23. Kaminker, P. et al. Higher-order nuclear organization in growth arrest of human mammary epithelial cells: a novel role for telomere-associated protein TIN2. J. Cell Sci. 118, 1321–1330 (2005).

    CAS  PubMed  Google Scholar 

  24. Oh, B. K., Kim, Y. J., Park, C. & Park, Y. N. Up-regulation of telomere-binding proteins, TRF1, TRF2, and TIN2 is related to telomere shortening during human multistep hepatocarcinogenesis. Am. J. Pathol. 166, 73–80 (2005). Telomere repeat binding proteins are shown to be vastly upregulated in human cancer, which indicates that these proteins could have a role in promoting tumorigenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gelmini, S. et al. Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer. Cancer Lett. 216, 81–87 (2004).

    CAS  PubMed  Google Scholar 

  26. Kondo, T. et al. Expression of POT1 is associated with tumor stage and telomere length in gastric carcinoma. Cancer Res. 64, 523–529 (2004).

    CAS  PubMed  Google Scholar 

  27. Miyachi, K. et al. Correlation between telomerase activity and telomeric-repeat binding factors in gastric cancer. J. Exp. Clin. Cancer Res. 21, 269–275 (2002).

    CAS  PubMed  Google Scholar 

  28. Matsutani, N. et al. Expression of telomeric repeat binding factor 1 and 2 and TRF1-interacting nuclear protein 2 in human gastric carcinomas. Int. J. Oncol. 19, 507–512 (2001).

    CAS  PubMed  Google Scholar 

  29. Zhu, X. D. et al. ERCC1/XPF removes the 3′ overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol. Cell 12, 1489–1498 (2003).

    CAS  PubMed  Google Scholar 

  30. Dantzer, F. et al. Functional interaction between poly(ADP-ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2. Mol. Cell. Biol. 24, 1595–1607 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 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  Google Scholar 

  32. Samper, E et al. Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep. 1, 244–252 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Goytisolo, F. A. et al. The absence of the DNA-dependent protein kinase catalytic subunit in mice results in anaphase bridges and in increased telomeric fusions with normal telomere length and G-strand overhang. Mol. Cell. Biol. 21, 3642–3651 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tarsounas, M. et al. Telomere maintenance requires the RAD51D recombination/repair protein. Cell 117, 337–347 (2004).

    CAS  PubMed  Google Scholar 

  35. Jaco, I. et al. Role of mammalian Rad54 in telomere length maintenance. Mol. Cell. Biol. 23, 5572–5580 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, R. C., Smogorzewska, A. & de Lange, T. Homologous recombination generates T-loop-sized deletions at human telomeres. Cell 119, 355–368 (2004). References 34–36 show a clear involvement of homologous recombination activities in telomere integrity and telomere length regulation.

    CAS  PubMed  Google Scholar 

  37. Bailey, S. M. et al. Strand-specific postreplicative processing of mammalian telomeres. Science 293, 2462–2465 (2001).

    CAS  PubMed  Google Scholar 

  38. Crabbe, 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  PubMed  Google Scholar 

  39. Espejel, S. et al. Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice. EMBO Rep. 5, 503–509 (2004).(2002a).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Espejel, S. et al. Mammalian Ku86 mediates chromosomal fusions and apoptosis caused by critically short telomeres. EMBO J. 21, 2207–2219 (2002a).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Espejel, S. et al. Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. EMBO J. 21, 6275–6287 (2002b).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bechter, O. E. et al. Telomeric recombination in mismatch repair deficient human colon cancer cells after telomerase inhibition. Cancer Res. 64, 3444–3451 (2004).

    CAS  PubMed  Google Scholar 

  43. Bradshaw, P. S., Stavropoulos, D. J. & Meyn, M. S. Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nature Genet. 37, 193–197 (2005). This paper shows that TRF2 can localize to non-telomeric DNA damage lesions produced by a laser track, which indicates a role for TRF2 in DNA damage repair.

    CAS  PubMed  Google Scholar 

  44. Karlseder, J. et al. The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol. 2, e240 (2004).

    PubMed  PubMed Central  Google Scholar 

  45. Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).

    CAS  PubMed  Google Scholar 

  46. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003).

    CAS  PubMed  Google Scholar 

  47. Lustig, A. J. Clues to catastrophic telomere loss in mammals from yeast telomere rapid deletion. Nature Rev. Genet. 4, 916–923 (2003).

    CAS  PubMed  Google Scholar 

  48. Goytisolo, F. A. et al. Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J. Exp. Med. 192, 1625–1636 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ranganathan, V. et al. Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit. Curr. Biol. 11, 962–966 (2001).

    CAS  PubMed  Google Scholar 

  50. Taylor, A. M., Groom, A. & Byrd, P. J. Ataxia-telangiectasia-like disorder (ATLD) — its clinical presentation and molecular basis. DNA repair 3, 1219–1225 (2004).

    CAS  PubMed  Google Scholar 

  51. Wyllie, F. S. et al. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nature Genet. 24, 16–17 (2000).

    CAS  PubMed  Google Scholar 

  52. de Boer, J. & Hoeijmakers, J. H. Nucleotide excision repair and human syndromes. Carcinogenesis 21, 453–460 (2000).

    CAS  PubMed  Google Scholar 

  53. Hande, M. P. et al. Extra-chromosomal telomeric DNA in cells from Atm−/− mice and patients with ataxia-telangiectasia. Hum. Mol. Genet. 10, 519–528 (2001).

    CAS  PubMed  Google Scholar 

  54. Holgersson, A., Nilsson, A., Lewensohn, R. & Kanter, L. Expression of DNA-PKcs and Ku86, but not Ku70, differs between lymphoid malignancies. Exp. Mol. Pathol. 77, 1–6 (2004).

    CAS  PubMed  Google Scholar 

  55. Gonzalez, R. et al. Loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and BRCA2 loci in breast cancer: pathological correlations. Br. J. Cancer 81, 503–509 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  57. Shay, J. W. & Wright, W. E. Telomerase: a target for cancer therapeutics. Cancer Cell 2, 257–265 (2002).

    CAS  PubMed  Google Scholar 

  58. Lin, S. Y. & Elledge, S. J. Multiple tumor suppressor pathways negatively regulate telomerase. Cell 113, 881–889 (2003).

    CAS  PubMed  Google Scholar 

  59. Blasco, M. A. Telomerase beyond telomeres. Nature Rev. Cancer 2, 627–632 (2002).

    CAS  Google Scholar 

  60. Henson, J. D., Neumann, A. A., Yeager, T. R. & Reddel, R. R. Alternative lengthening of telomeres in mammalian cells. Oncogene 21, 598–610 (2002).

    CAS  PubMed  Google Scholar 

  61. Lundblad, V. Telomere maintenance without telomerase. Oncogene 21, 522–531 (2002).

    CAS  PubMed  Google Scholar 

  62. Dunham, M. A., Neumann, A. A., Fasching, C. L. & Reddel, R. R. Telomere maintenance by recombination in human cells. Nature Genet. 26, 447–450 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  66. Blasco, M. A. Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging. EMBO J. 24, 1095–1103 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Herrera, E. et al. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950–2960 (1999a).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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 (1999b).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Herrera, E., Martinez, A. C. & Blasco, M. A. Impaired germinal center reaction in mice with short telomeres. EMBO J. 19, 472–481 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Franco, S., Segura, I., Riese, H. & Blasco, M. A. Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeres. Cancer Res. 62, 552–559 (2002).

    CAS  PubMed  Google Scholar 

  71. Ferron, S. et al. Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131, 4059–4070 (2004).

    CAS  PubMed  Google Scholar 

  72. Leri, A. et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22, 131–139 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Samper, E. et al. Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood 99, 2767–2775 (2002).

    CAS  PubMed  Google Scholar 

  74. Gonzalez-Suarez, E., Samper, E., Flores, J. M. & Blasco, M. A. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nature Genet. 26, 114–117 (2000). This manuscript showed for the first time that short telomeres in the absence of telomerase provide a potent tumour-suppression mechanism in response to carcinogenic treatments.

    CAS  PubMed  Google Scholar 

  75. Poch, E. et al. Short telomeres protect from diet-induced atherosclerosis in apolipoprotein E-null mice. FASEB J. 18, 418–420 (2004).

    CAS  PubMed  Google Scholar 

  76. Samper, E., Flores, J. M. & Blasco, M. A. Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc −/− mice with short telomeres. EMBO Rep. 2, 1–8 (2001). This paper demonstrates that short telomeres in the absence of telomerase are the direct cause of chromosomal aberrations and premature ageing in the context of the telomerase-deficient mouse model, as both premature ageing and chromosomal instability can be prevented by telomerase reintroduction and rescue of short telomeres.

    Google Scholar 

  77. Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).

    CAS  PubMed  Google Scholar 

  78. Rudolph, K. L., Millard, M., Bosenberg, M. W. & DePinho, R. A. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nature Genet. 28, 155–159 (2001).

    CAS  PubMed  Google Scholar 

  79. Greenberg, R. A. et al. Short dysfunctional telomeres impair tumorigenesis in the INK4a(δ2/3) cancer-prone mouse. Cell 97, 515–525 (1999).

    CAS  PubMed  Google Scholar 

  80. Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. González-Suárez, E., Flores, J. M. & Blasco, M. A. Cooperation between p53 mutation and high telomerase transgenic expression in spontaneous cancer development. Mol. Cell. Biol. 22, 7291–7301 (2002).

    PubMed  PubMed Central  Google Scholar 

  82. González-Suárez, E., Geserick, C., Flores, J. M. & Blasco, M. A. Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene 24, 2256–22570 (2005).

    PubMed  Google Scholar 

  83. Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Canela, A., Martín-Caballero, J., Flores, J. M. & Blasco, M. A. Constitutive expression of Tert in thymocytes leads to increased incidence and dissemination of T-cell lymphoma in Lck-Tert mice. Mol. Cell. Biol. 24, 4275–4293 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Oh, H. et al. Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival. Proc. Natl Acad. Sci. USA 98, 10308–10313 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Cayuela, M. L., Flores, J. M. & Blasco, M. A. The telomerase RNA component Terc is required for the tumour-promoting effects of Tert overexpression. EMBO Rep. 6, 268–274 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Oh, H. et al. Telomere attrition and Chk2 activation in human heart failure. Proc. Natl Acad. Sci. USA 100, 5378–5383 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. O'Sullivan, J. N. et al. Chromosomal instability in ulcerative colitis is related to telomere shortening. Nature Genet. 32, 280–284 (2002).

    CAS  PubMed  Google Scholar 

  89. Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002).

    CAS  PubMed  Google Scholar 

  90. Samani, N. J., Boultby, R., Butler, R., Thompson, J. R. & Goodall, A. H. Telomere shortening in atherosclerosis. Lancet 358, 472–473 (2001).

    CAS  PubMed  Google Scholar 

  91. Cawthon, R. M., Smith, K. R., O'Brien, E., Sivatchenko, A. & Kerber, R. A. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–365 (2003). This paper shows that telomere length in aged individuals is predictive of the time to death caused by heart disease and infections.

    CAS  PubMed  Google Scholar 

  92. Epel, E. S. et al. Accelerated telomere shortening in response to life stress. Proc. Natl Acad. Sci. USA 101, 17312–17315 (2004). A negative correlation between telomerase activity levels and telomere length in blood cells is described for women exposed to perceived stress.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  95. Vulliamy, T. et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nature Genet. 36, 447–449 (2004). A correlation between disease presentation and telomere length is observed in families with dyskeratosis congenita.

    CAS  PubMed  Google Scholar 

  96. 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  Google Scholar 

  97. Marrone, A. et al. Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood 104, 3936–3342 (2004).

    CAS  PubMed  Google Scholar 

  98. Tahara, H. et al. Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein–Barr virus. Oncogene 15, 1911–1920 (1997).

    CAS  PubMed  Google Scholar 

  99. Tchirkov, A. & Lansdorp, P. M. Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia. Hum. Mol. Genet. 12, 227–327 (2003).

    CAS  PubMed  Google Scholar 

  100. Lebel, M & Leder, P. A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc. Natl Acad. Sci. USA 95, 13097–13102 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Chester, N., Kuo, F., Kozak, C., O'Hara, C. D. & Leder, P. Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom's syndrome gene. Genes Dev. 12, 3382–3393 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 159–171 (1996).

    CAS  PubMed  Google Scholar 

  103. Koomen, M. et al. Reduced fertility and hypersensitivity to mitomycin C characterize Fancg/Xrcc9 null mice. Hum. Mol. Genet. 11, 273–281 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  106. 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  Google Scholar 

  107. Franco, S. et al. Telomere dynamics in Fancg-deficient mouse and human cells. Blood 104, 3927–3935 (2004).

    CAS  PubMed  Google Scholar 

  108. Mochizuki, Y. et al. Mouse dyskerin mutations affect accumulation of telomerase RNA and small nucleolar RNA, telomerase activity, and ribosomal RNA processing. Proc. Natl Acad. Sci. USA 101, 10756–10761 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Espejel, S. et al. Impact of telomerase ablation on organismal viability, aging, and tumorigenesis in mice lacking the DNA repair proteins PARP-1, Ku86, or DNA-PKcs. J. Cell Biol. 167, 627–638 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Acknowledgements

I would like to thank P. Muñoz, S. Gonzalo and I. Flores for critical reading of this manuscript. M.A.B.'s laboratory is funded by the Spanish Ministery of Culture and Science, the Regional Government of Madrid, the European Union and the Josef Steiner Cancer Research Award 2003.

Author information

Authors and Affiliations

  1. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), 28029, Madrid, Spain

    Maria A. Blasco

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  1. Maria A. Blasco
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DATABASES

Entrez gene

BLM

DKC1

MRE11

NBN

Tert

Trf1

WRN

Omim

Ataxia telangiectasia

Ataxia-telangiectasia-like disorder

Bloom syndrome

Dyskeratosis congenita

Fanconi anaemia

Nijmegen breakage syndrome

Rett syndrome

Werner syndrome

Xeroderma pigmentosum syndrome

SwissProt

ATM

HP1α

POT1

RB1

RBL1

RBL2

SUV39H1

SUV39H2

TIN2

TRF1

TRF2

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Glossary

NUCLEOSOME

The structure responsible in part for the compactness of a chromosome. Each nucleosome consists of a sequence of DNA wrapped around a histone core.

HETEROCHROMATIN

Chromosomal material that is tightly coiled and inactive in terms of gene expression.

SATELLITE REPEATS

DNA that contains many tandem repeats of a short basic repeating unit. Both the major and minor satellite repeats are located at pericentric heterochromatin.

RETINOBLASTOMA PROTEINS

These are a family of tumour supressor proteins that share a similar structure and function. Mutations in RB1 have been associated with retinoblastoma, a malignant eye tumour in children.

RETT SYNDROME

An X-linked dominant neurological disorder that affects girls only and is one of the most common causes of mental retardation in females. Rett syndrome is due to a mutation in the MECP2 gene (methyl-CpG-binding protein 2).

ANTICIPATION

A phenomenon in which a genetic disease appears earlier in the lifetime of an individual with each successive generation.

MITOTIC CATASTROPHE

The loss of cell viability that results from the attempted aberrant chromosome segregation in the presence of severe cellular damage (for example, short telomeres).

snoRNA

Small nucleolar RNAs. The functions of these snoRNAs include RNA cleavage reactions, as well as specifying sites of ribose methylation and pseudouridylation. Mutations in DKC1 (dyskeratosis congenita 1, dyskerin) result in defective pseudouridylation of the H/ACA box class of snoRNAs.

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Blasco, M. Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet 6, 611–622 (2005). https://doi.org/10.1038/nrg1656

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