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.

  • Article
  • Published:

XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer

Nature Genetics volume 37, pages 1063–1071 (2005)Cite this article

Abstract

TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.

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: Increased TRF2 expression in K5-Terf2 mice.
Figure 2: Skin phenotypes in K5-Terf2 mice.
Figure 3: Increased TERF2 expression in human skin tumors.
Figure 4: Hypersensitivity of K5-Terf2 mice to UVB irradiation and MMC.
Figure 5: Increased UV-induced carcinogenesis in K5-Terf2 mice.
Figure 6: Telomere shortening in K5-Terf2 mice.
Figure 7: The short telomere phenotype of K5-Terf2 mice is telomerase-independent.
Figure 8: Telomere shortening and telomere damage in K5-Terf2 mice is XPF-dependent.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Garcia-Cao, M., O'Sullivan, R., Peters, A.H., Jenuwein, T. & Blasco, M.A. Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat. Genet. 36, 94–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Wang, R.C., Smogorzewska, A. & de Lange, T. Homologous recombination generates T-loop-sized deletions at human telomeres. Cell 119, 355–368 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Chan, S.W. & Blackburn, E.H. New ways not to make ends meet: telomerase, DNA damage proteins and heterochromatin. Oncogene 21, 553–563 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Goytisolo, F.A. & Blasco, M.A. Many ways to telomere dysfunction: in vivo studies using mouse models. Oncogene 21, 584–591 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. 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. Nat. Genet. 37, 193–197 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Zhu, X.D., Kuster, B., Mann, M., Petrini, J.H. & Lange, T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat. Genet. 25, 347–352 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  13. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Murillas, R. et al. Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations on hair follicle development and skin structure. EMBO J. 14, 5216–5223 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. González-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).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Berneburg, M. & Lehmann, A.R. Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. Adv. Genet. 43, 71–102 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. de Laat, W.L., Jaspers, N.G. & Hoeijmakers, J.H. Molecular mechanism of nucleotide excision repair. Genes Dev. 13, 768–785 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Petit, C. & Sancar, A. Nucleotide excision repair: from E. coli to man. Biochimie 81, 15–25 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Mu, D. et al. DNA interstrand cross-links induce futile repair synthesis in mammalian cell extracts. Mol. Cell. Biol. 20, 2446–2454 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McWhir, J., Selfridge, J., Harrison, D.J., Squires, S. & Melton, D.W. Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nat. Genet. 5, 217–224 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Weeda, G. et al. Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. Curr. Biol. 7, 427–439 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Tian, M., Shinkura, R., Shinkura, N. & Alt, F.W. Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF. Mol. Cell. Biol. 24, 1200–1205 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Nakane, H. et al. High incidence of ultraviolet-B or chemical-carcinogen-induced skin tumors in mice lacking the xeroderma pigmentosum group A gene. Nature 377, 165–168 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Sands, A.T., Abuin, A., Sánchez, A., Conti, C.J. & Bradley, A. susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC. Nature 377, 162–165 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. González-Suárez, E., Samper, E., Flores, J.M. & Blasco, M.A. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat. Genet. 26, 114–117 (2000).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Modesti, M. & Kanaar, R. DNA repair: spot(light)s on chromatin. Curr. Biol. 11, R229–R232 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vogel, H., Lim, D.S., Karsenty, G., Finegold, M. & Hasty, P. Deletion of Ku86 causes early onset of senescence in mice. Proc. Natl. Acad. Sci. USA 96, 10770–10775 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bessler, M., Wilson, D.B. & Mason, P.J. Dyskeratosis congenita and telomerase. Curr. Opin. Pediatr. 16, 23–28 (2004).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F.W. Alt for the XPF-deficient mice; E. Gilson for advice; M. Morente and J. García-Solano for collecting the different human tumor samples; R. Serrano for mouse work; E. Santos and J. Freire for genotyping; and M. Serrano and I. Flores for critical reading of the manuscript. P.M. is a Ramon y Cajal senior scientist. R.B. is a predoctoral fellow founded by the Spanish National Cancer Centre. The laboratory of M.A.B. is funded by the Spanish Ministry of Education and Science, the Regional Government of Madrid, the European Union and the Josef Steiner Award 2003.

Author information

Author notes

  1. Purificación Muñoz and Raquel Blanco: These authors contributed equally to this work.

Authors and Affiliations

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

    Purificación Muñoz, Raquel Blanco & María A Blasco

  2. Animal Surgery and Medicine Department, Facultad de Veterinaria, Universidad Complutense de Madrid, Madrid, Spain

    Juana M Flores

Authors
  1. Purificación Muñoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raquel Blanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Juana M Flores
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. María A Blasco
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María A Blasco.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Lethality associated to high TRF2 levels. (PDF 294 kb)

Supplementary Fig. 2

Histopathology of wild type and K5TRF2 skin sections (tail and ear). (PDF 2823 kb)

Supplementary Fig. 3

Effect of hair protection from light on telomere shortening produced by increased TRF2. (PDF 270 kb)

Supplementary Fig. 4

Decreased telomere length and increased chromosomal instability in K5TRF2 keratinocytes. (PDF 2365 kb)

Supplementary Fig. 5

Increased constitutive γH2AX foci in the tail skin of K5TRF2 mice. (PDF 3324 kb)

Supplementary Table 1

Frequency of chromosomal aberrations per metaphase in primary keratinocytes of the indicated genotypes as determined by Q-FISH. (PDF 59 kb)

Supplementary Table 2

Histopathological analysis of skin lesions in UV-irradiated K5TRF2 mice at time of death. (PDF 37 kb)

Supplementary Table 3

Primers used for RT-PCR reactions and genotyping. (PDF 21 kb)

Supplementary Methods (PDF 44 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Muñoz, P., Blanco, R., Flores, J. et al. XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer. Nat Genet 37, 1063–1071 (2005). https://doi.org/10.1038/ng1633

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1633

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