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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.

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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.

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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.

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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

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  1. Purificación Muñoz
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  2. Raquel Blanco
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  3. Juana M Flores
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  4. María A Blasco
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Corresponding author

Correspondence to María A Blasco.

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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)

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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

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