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.

  • Letter
  • Published:

DNA methyltransferases control telomere length and telomere recombination in mammalian cells

Nature Cell Biology volume 8, pages 416–424 (2006)Cite this article

Abstract

Here, we describe a role for mammalian DNA methyltransferases (DNMTs) in telomere length control. Mouse embryonic stem (ES) cells genetically deficient for DNMT1, or both DNMT3a and DNMT3b have dramatically elongated telomeres compared with wild-type controls. Mammalian telomere repeats (TTAGGG) lack the canonical CpG methylation site. However, we demonstrate that mouse subtelomeric regions are heavily methylated, and that this modification is decreased in DNMT-deficient cells. We show that other heterochromatic marks, such as histone 3 Lys 9 (H3K9) and histone 4 Lys 20 (H4K20) trimethylation, remain at both subtelomeric and telomeric regions in these cells. Lack of DNMTs also resulted in increased telomeric recombination as indicated by sister-chromatid exchanges involving telomeric sequences, and by the presence of 'alternative lengthening of telomeres' (ALT)-associated promyelocytic leukaemia (PML) bodies (APBs). This increased telomeric recombination may lead to telomere-length changes, although our results do not exclude a potential involvement of telomerase and telomere-binding proteins in the aberrant telomere elongation observed in DNMT-deficient cells. Together, these results demonstrate a previously unappreciated role for DNA methylation in maintaining telomere integrity.

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: Deregulation of telomere length in ES cells deficient for DNA methyltransferase activities.
Figure 2: Decreased DNA methylation levels in cells lacking DNA methyltransferase activities.
Figure 3: Subtelomeric and telomeric chromatin features of DNMT-deficient ES cells.
Figure 4: Increased telomeric sister-chromatid exchange in DNMT-deficient cells.
Figure 5: Increased APBs in DNMT-deficient cells.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Blasco, M. A. Telomeres and human disease: cancer, ageing and beyond. Nature Rev. Genet. 6, 611–622 (2005).

    Article  CAS  Google Scholar 

  5. Muntoni, A. & Reddel, R. R. The first molecular details of ALT in human tumor cells. Hum. Mol. Genet. 14, 191–196 (2005).

    Article  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. Bechter, O. E., Zou, Y., Walker, W., Wright, W. E. & Shay, J. W. Telomeric recombination in mismatch repair deficient human colon cancer cells and telomerase inhibition. Cancer Res. 64, 3444–3451 (2004).

    Article  CAS  Google Scholar 

  8. Bailey, S. M., Brenneman, M. A. & Goodwin, E. H. Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. Nucleic Acids Res. 32, 3743–3751 (2004).

    Article  CAS  Google Scholar 

  9. Blasco, M. A. Telomere epigenetics: a higher-order control of telomere length in mammalian cells. Carcinogenesis 25, 1083–1087 (2004).

    Article  CAS  Google Scholar 

  10. Gonzalo, S. & Blasco, M. A. Role of Rb family in the epigenetic definition of chromatin. Cell Cycle 4, 752–755 (2005).

    Article  CAS  Google Scholar 

  11. 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. Nature Genet. 36, 94–99 (2004).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Li, E., Beard, C. & Jaenisch, R. Role for DNA methylation in genomic imprinting. Nature 366, 362–365 (1993).

    Article  CAS  Google Scholar 

  15. Esteller, M. Relevance of DNA methylation in the management of cancer. Lancet Oncol. 4, 351–358 (2003).

    Article  CAS  Google Scholar 

  16. Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).

    Article  CAS  Google Scholar 

  17. Okano, M., Xie, S. & Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nature Genet. 19, 219–220 (1998).

    Article  CAS  Google Scholar 

  18. Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    Article  CAS  Google Scholar 

  19. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  Google Scholar 

  20. Chen, T., Ueda, Y., Dodge, J. E., Wang, Z. & Li, E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell Biol. 23, 5594–5605 (2003).

    Article  CAS  Google Scholar 

  21. Chen, T., Tsujimoto, N. & Li, E. The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol. Cell Biol. 24, 9048–9058 (2004).

    Article  CAS  Google Scholar 

  22. Dodge, J. E. et al. Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J. Biol. Chem. 280, 17986–17991 (2005).

    Article  CAS  Google Scholar 

  23. Brock, G. J., Charlton, J. & Bird, A. Densely methylated sequences that are preferentially localized at telomere-proximal regions of human chromosomes. Gene 240, 269–277 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Steinert, S., Shay, J. W. & Wright, W. E. Modification of subtelomeric DNA. Mol. Cell Biol. 24, 4571–4580 (2004).

    Article  CAS  Google Scholar 

  26. Dominguez-Bendala, J. & McWhir, J. Enhanced gene targeting frequency in ES cells with low genomic methylation levels. Transgenic Res. 13, 69–74 (2004).

    Article  CAS  Google Scholar 

  27. Maloisel, L. & Rossignol, J. L. Suppression of crossing-over by DNA methylation in Ascobolus. Genes Dev. 12, 1381–1389 (1998).

    Article  CAS  Google Scholar 

  28. Bender, J. Cytosine methylation of repeated sequences in eukaryotes: the role of DNA pairing. Trends Biochem. Sci. 23, 252–256 (1998).

    Article  CAS  Google Scholar 

  29. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005).

    Article  CAS  Google Scholar 

  30. Samper, E., Goytisolo, F. A., Slijepcevic, P., van Buul, P. P. & Blasco, M. A. Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep. 1, 244–252 (2000).

    Article  CAS  Google Scholar 

  31. Zijlmans, M. et al. Telomeres in the mouse have large inter-chromosomal variations in the number of T2AG3 repeats. Proc. Natl Acad. Sci. USA 94, 7423–7428 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. Fraga, M. F. et al. High-performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues. Electrophoresis 23, 1677–1681 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

S.G. is a Fondo de Investigaciones Sanitarias (FIS) senior scientist. I. J. is a student of the Gulbenkian PhD Program in Biomedicine and is supported by Fundacão para la Ciěncia e Tecnologia/Ministério da Ciěncia e Ensino Superior (FCT/MCT; Portugal). M.E. is funded by the Ministry of Science and Technology of Spain (MCYT; T08-03) and the European Union (CCEE04-00). M.A.B. is funded by the MCYT (SAF2005-00277, GEN2001-4856-C13-08), the regional government of Madrid (GR/SAL/0597/2004), the European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842) 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), Madrid, E-28029, Spain

    Susana Gonzalo, Isabel Jaco & María A. Blasco

  2. Epigenetics Group, Molecular Pathology Program, Spanish National Cancer Centre (CNIO), Madrid, E-28029, Spain

    Mario F. Fraga & Manel Esteller

  3. Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, 02139, MA, USA

    Taiping Chen & En Li

Authors
  1. Susana Gonzalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabel Jaco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mario F. Fraga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Taiping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. En Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manel Esteller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. 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 Information

Supplementary Figures S1, S2, S3, Table 1 and Supplementary Text (PDF 673 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gonzalo, S., Jaco, I., Fraga, M. et al. DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8, 416–424 (2006). https://doi.org/10.1038/ncb1386

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1386

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