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:

Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination

Nature Cell Biology volume 8, pages 885–890 (2006)Cite this article

Abstract

Ku70–Ku80 heterodimers promote the non-homologous end-joining (NHEJ) of DNA breaks and, as shown here, the fusion of dysfunctional telomeres. Paradoxically, this heterodimer is also located at functional mammalian telomeres and interacts with components of shelterin, the protein complex that protects telomeres1,2,3,4,5,6. To determine whether Ku contributes to telomere protection, we analysed Ku70−/− mouse cells7. Telomeres of Ku70−/− cells had a normal DNA structure and did not activate a DNA damage signal. However, Ku70 repressed exchanges between sister telomeres — a form of homologous recombination implicated in the alternative lengthening of telomeres (ALT) pathway8. Sister telomere exchanges occurred at approximately 15% of the chromosome ends when Ku70 and the telomeric protein TRF2 were absent. Combined deficiency of TRF2 and another NHEJ factor, DNA ligase IV, did not elicit this phenotype. Sister telomere exchanges were not elevated at telomeres with functional TRF2, indicating that TRF2 and Ku70 act in parallel to repress recombination. We conclude that mammalian chromosome ends are highly susceptible to homologous recombination, which can endanger cell viability if an unequal exchange generates a critically shortened telomere. Therefore, Ku- and TRF2-mediated repression of homologous recombination is an important aspect of telomere protection.

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: Ku70 stimulates fusion of dysfunctional telomeres.
Figure 2: Absence of a significant telomere DNA damage signal in Ku70−/− cells.
Figure 3: Induction of T-SCEs in absence of TRF2 and Ku70.
Figure 4: Schematic representation of the roles of TRF2 and Ku70 in repressing DSB repair at mammalian telomeres.

Similar content being viewed by others

References

  1. Hsu, H. L., Gilley, D., Blackburn, E. H. & Chen, D. J. Ku is associated with the telomere in mammals. Proc. Natl Acad. Sci. USA 96, 12454–12458 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Hsu, H. L. et al. Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev. 14, 2807–2812 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Song, K., Jung, D., Jung, Y., Lee, S. G. & Lee, I. Interaction of human Ku70 with TRF2. FEBS Lett. 481, 81–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. d'Adda di Fagagna, F. et al. Effects of DNA nonhomologous end-joining factors on telomere length and chromosomal stability in mammalian cells. Curr. Biol. 11, 1192–1116 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Gilley, D. et al. DNA-PKcs is critical for telomere capping. Proc. Natl Acad. Sci. USA 98, 15084–15088 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. O'Connor, M. S., Safari, A., Liu, D., Qin, J. & Songyang, Z. The human Rap1 protein complex and modulation of telomere length. J. Biol. Chem. 279, 28585–28591 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Gu, Y. et al. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity 7, 653–665 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Celli, G. & de Lange, T. DNA processing not required for ATM-mediated telomere damage response after TRF2 deletion. Nature Cell Biol. 7, 712–718 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Smogorzewska, A. & de Lange, T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 21, 4338–4348 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Ma, J. L., Kim, E. M., Haber, J. E. & Lee, S. E. Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol. Cell. Biol. 23, 8820–8828 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Walker, J. R., Corpina, R. A. & Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412, 607–614 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Stansel, R. M., de Lange, T. & Griffith, J. D. T-loop assembly in vitro involves binding of TRF2 near the 3′ telomeric overhang. EMBO J. 20, 5532–5540 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Bertuch, A. A. & Lundblad, V. Which end: dissecting Ku's function at telomeres and double-strand breaks. Genes Dev. 17, 2347–2350 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Riha, K., Watson, J. M., Parkey, J. & Shippen, D. E. Telomere length deregulation and enhanced sensitivity to genotoxic stress in Arabidopsis mutants deficient in Ku70. EMBO J. 21, 2819–2826 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. 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  PubMed Central  PubMed  Google Scholar 

  20. 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 

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

    Article  CAS  PubMed  Google Scholar 

  22. 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  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  24. Bailey, S. M., Cornforth, M. N., Kurimasa, A., Chen, D. J. & Goodwin, E. H. Strand-specific postreplicative processing of mammalian telomeres. Science 293, 2462–2465 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Wang, Y. et al. An increase in telomere sister chromatid exchange in murine embryonic stem cells possessing critically shortened telomeres. Proc. Natl Acad. Sci. USA 102, 10256–10260 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Laud, P. R. et al. Elevated telomere-telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 19, 2560–2570 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. 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 

  28. Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Weinstock, D. M. & Jasin, M. Alternative pathways for the repair of RAG-induced DNA breaks. Mol. Cell. Biol. 26, 131–139 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Adachi, N., Ishino, T., Ishii, Y., Takeda, S. & Koyama, H. DNA ligase IV-deficient cells are more resistant to ionizing radiation in the absence of Ku70: Implications for DNA double-strand break repair. Proc. Natl Acad. Sci. USA 98, 12109–12113 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. 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 

  32. Polotnianka, R. M., Li, J. & Lustig, A. J. The yeast Ku heterodimer is essential for protection of the telomere against nucleolytic and recombinational activities. Curr. Biol. 8, 831–834 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Baumann, P. & Cech, T. R. Protection of telomeres by the Ku protein in fission yeast. Mol. Biol. Cell 11, 3265–3275 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Bianchi, A. & de Lange, T. Ku binds telomeric DNA in vitro. J. Biol. Chem. 274, 21223–21227 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Li, G., Nelsen, C. & Hendrickson, E. A. Ku86 is essential in human somatic cells. Proc. Natl Acad. Sci. USA 99, 832–837 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to F. Alt for providing the Ku70 and DNA ligase IV knockout mice and to D. White for mouse husbandry. T. Halazonetis is thanked for generous gifts of the 53BP1 antibody. G.B.C. was supported by the Leukemia and Lymphoma Society. E.L.D. was supported by an Irma T. Hirschl fellowship. This work was supported by a grant from the National Institutes of Health (GM49046).

Author information

Author notes

  1. Giulia B. Celli

    Present address: Skirball Institute of Biomolecular Medicine, NYU School of Medicine, New York, NY

  2. Giulia B. Celli and Eros Lazzerini Denchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, 10021, NY, USA

    Giulia B. Celli, Eros Lazzerini Denchi & Titia de Lange

Authors
  1. Giulia B. Celli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eros Lazzerini Denchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Titia de Lange
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Titia de Lange.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figure S1 (PDF 112 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Celli, G., Denchi, E. & de Lange, T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat Cell Biol 8, 885–890 (2006). https://doi.org/10.1038/ncb1444

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1444

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