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:

Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation

Nature Cell Biology volume 7, pages 706–711 (2005)Cite this article

Abstract

Telomeres protect chromosome ends from fusion, degradation and recombination. Loss of telomere function has opposite effects on tumorigenesis: apoptosis, which inhibits tumour growth, and genomic instability, which accelerates tumour formation. Here we describe a new mechanism by which short telomeres inhibit tumorigenesis through interference with oncogenic translocations. In mice that are null for both ataxia-telangiectasia-mutated (Atm) and telomerase RNA (mTR), the first generation (G1) Atm−/− mTR−/− mice have a lower rate of tumour formation than Atm−/− mTR+/+ mice. These Atm−/− mTR−/− G1 tumours show no increase in either apoptosis or overall genomic instability. Strikingly, the tumours show a high fraction of translocations containing telomere signals at the translocation junctions. Translocations of the T-cell receptors on chromosome 14, which initiate tumorigenesis, were interrupted by fusion with telomeres. Telomere repeats were also detected at the translocation junctions in pre-malignant thymocytes. We propose that telomere fusion to DNA double-strand breaks competes with the generation of oncogenic translocations and thus reduces tumour formation.

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: Atm−/− mTR−/− G1 mice have increased survival and reduced tumorigenesis.
Figure 2: No increase in cell death or defects in proliferation in Atm−/− mTR−/− G1 tumours.
Figure 3: Telomere length and signal-free ends in Atm−/− mTR−/− tumours and normal B cells.
Figure 4: Telomere-mediated translocations in Atm−/− mTR−/− tumours.
Figure 5: Translocation events in normal thymocytes and a model for telomere interference in the generation of oncogenic translocations.

Similar content being viewed by others

References

  1. Mills, K. D., Ferguson, D. O. & Alt, F. W. The role of DNA breaks in genomic instability and tumorigenesis. Immunol. Rev. 194, 77–95 (2003).

    Article  CAS  Google Scholar 

  2. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Liyanage, M. et al. Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice. Blood 96, 1940–1946 (2000).

    CAS  PubMed  Google Scholar 

  5. Greenwell, P. W. et al. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell 82, 823–829 (1995).

    Article  CAS  Google Scholar 

  6. Morrow, D. M., Tagle, D. A., Shiloh, Y., Collins, F. S. & Hieter, P. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82, 831–840 (1995).

    Article  CAS  Google Scholar 

  7. Myung, K., Chen, C. & Kolodner, R. D. Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 411, 1073–1076 (2001).

    Article  CAS  Google Scholar 

  8. DuBois, M. L., Haimberger, Z. W., McIntosh, M. W. & Gottschling, D. E. A quantitative assay for telomere protection in Saccharomyces cerevisiae. Genetics 161, 995–1013 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chan, S. W. & Blackburn, E. H. Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol. Cell 11, 1379–1387 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Qi, L. et al. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. Cancer Res. 63, 8188–8196 (2003).

    CAS  PubMed  Google Scholar 

  13. Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002).

    Article  CAS  Google Scholar 

  14. Feldser, D. M., Hackett, J. A. & Greider, C. W. Telomere dysfunction and the initiation of genome instability. Nature Rev. Cancer 3, 623–627 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999).

    Article  CAS  Google Scholar 

  19. 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).

    Article  CAS  Google Scholar 

  20. Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. Latre, L. et al. Shortened telomeres join to DNA breaks interfering with their correct repair. Exp. Cell Res. 287, 282–288 (2003).

    Article  CAS  Google Scholar 

  25. Bailey, S. M., Cornforth, M. N., Ullrich, R. L. & Goodwin, E. H. Dysfunctional mammalian telomeres join with DNA double-strand breaks. DNA Repair (Amst.) 3, 349–357 (2004).

    Article  CAS  Google Scholar 

  26. Richardson, C. & Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000).

    Article  CAS  Google Scholar 

  27. Bassing, C. H., Swat, W. & Alt, F. W. The mechanism and regulation of chromosomal V(D)J recombination. Cell 109 Suppl., S45–S55 (2002).

    Article  CAS  Google Scholar 

  28. Kaplan, E. L. & Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457–481 (1958).

    Article  Google Scholar 

  29. Lansdorp, P. M. et al. Heterogeneity in telomere length of human chromosomes. Hum. Mol. Genet. 5, 685–691 (1996).

    Article  CAS  Google Scholar 

  30. Liyanage, M. et al. Multicolour spectral karyotyping of mouse chromosomes. Nature Genet. 14, 312–315 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to T. Ried and M. Difilippantonio for providing TCRα/δ BAC clones; M. Montminy for support; B. Todd and L. Y. Hao for assistance; R. Thompson for statistic consultation; Greider laboratory members, J. Boeke, G. Seydoux, G. Stetten, and R. Yarrington for critical reading of the manuscript. L.Q. is the 2nd Dr George Santos Researcher and Fellow of the Leukemia and Lymphoma Society (5532-03). B.O.K. is supported by a NIH training grant RR07002. This work is supported by NIH grants CA16519 (to C.W.G.) and RR00171 (to D.L.H.).

Author information

Author notes

  1. Ling Qi

    Present address: Peptide Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Ling Qi, Margaret A. Strong & Carol W. Greider

  2. Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Baktiar O. Karim & David L. Huso

Authors
  1. Ling Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margaret A. Strong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baktiar O. Karim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David L. Huso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carol W. Greider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carol W. Greider.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1 and S2; supplementary tables S1 and S2 (PDF 216 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qi, L., Strong, M., Karim, B. et al. Telomere fusion to chromosome breaks reduces oncogenic translocations and tumour formation. Nat Cell Biol 7, 706–711 (2005). https://doi.org/10.1038/ncb1276

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1276

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