Skip to main content

Thank you for visiting 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.

Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1


When telomeres are rendered dysfunctional through replicative attrition of the telomeric DNA or by inhibition of shelterin1, cells show the hallmarks of ataxia telangiectasia mutated (ATM) kinase signalling2,3,4. In addition, dysfunctional telomeres might induce an ATM-independent pathway, such as ataxia telangiectasia and Rad3-related (ATR) kinase signalling, as indicated by the phosphorylation of the ATR target CHK1 in senescent cells2,5 and the response of ATM-deficient cells to telomere dysfunction6,7. However, because telomere attrition is accompanied by secondary DNA damage, it has remained unclear whether there is an ATM-independent pathway for the detection of damaged telomeres. Here we show that damaged mammalian telomeres can activate both ATM and ATR and address the mechanism by which the shelterin complex represses these two important DNA damage signalling pathways. We analysed the telomere damage response on depletion of either or both of the shelterin proteins telomeric repeat binding factor 2 (TRF2) and protection of telomeres 1 (POT1) from cells lacking ATM and/or ATR kinase signalling. The data indicate that TRF2 and POT1 act independently to repress these two DNA damage response pathways. TRF2 represses ATM, whereas POT1 prevents activation of ATR. Unexpectedly, we found that either ATM or ATR signalling is required for efficient non-homologous end-joining of dysfunctional telomeres. The results reveal how mammalian telomeres use multiple mechanisms to avoid DNA damage surveillance and provide an explanation for the induction of replicative senescence and genome instability by shortened telomeres.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: TRF2 deletion activates ATM, not ATR.
Figure 2: POT1 inhibition activates ATR.
Figure 3: ATR activation in Terf2 –/– Atm –/– cells on inhibition of POT1a.
Figure 4: Role of POT1 and ATR in NHEJ of telomeres lacking TRF2.


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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  3. Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321–1325 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol. Cell 14, 501–513 (2004)

    Article  CAS  Google Scholar 

  6. 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 

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

    Article  ADS  CAS  Google Scholar 

  8. Celli, G. B. & 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Lazzerini Denchi, E., Celli, G. & de Lange, T. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication. Genes Dev. 20, 2648–2653 (2006)

    Article  Google Scholar 

  12. Jazayeri, A. et al. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nature Cell Biol. 8, 37–45 (2006)

    Article  CAS  Google Scholar 

  13. Dimitrova, N. & de Lange, T. MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes Dev. 20, 3238–3243 (2006)

    Article  CAS  Google Scholar 

  14. Zou, L. & Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542–1548 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Bertuch, A. A. & Lundblad, V. The maintenance and masking of chromosome termini. Curr. Opin. Cell Biol. 18, 247–253 (2006)

    Article  CAS  Google Scholar 

  16. Enomoto, S., Glowczewski, L. & Berman, J. MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. Mol. Biol. Cell 13, 2626–2638 (2002)

    Article  CAS  Google Scholar 

  17. Garvik, B., Carson, M. & Hartwell, L. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint. Mol. Cell. Biol. 15, 6128–6138 (1995)

    Article  CAS  Google Scholar 

  18. Hockemeyer, D., Daniels, J. P., Takai, H. & de Lange, T. Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell 126, 63–77 (2006)

    Article  CAS  Google Scholar 

  19. Wu, L. et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 126, 49–62 (2006)

    Article  CAS  Google Scholar 

  20. Brown, E. J. & Baltimore, D. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17, 615–628 (2003)

    Article  CAS  Google Scholar 

  21. Hockemeyer, D. et al. Telomere protection by mammalian POT1 requires interaction with TPP1. Nature Struct. Mol. Biol. advanced online publication, doi:10.1038/nsmb1270 (15 July 2007)

  22. Cortez, D., Guntuku, S., Qin, J. & Elledge, S. J. ATR and ATRIP: partners in checkpoint signaling. Science 294, 1713–1716 (2001)

    Article  ADS  CAS  Google Scholar 

  23. Hockemeyer, D., Sfeir, A. J., Shay, J. W., Wright, W. E. & de Lange, T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J. 24, 2667–2678 (2005)

    Article  CAS  Google Scholar 

  24. Karlseder, J. et al. The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol. 2, E240 (2004)

    Article  Google Scholar 

  25. Loayza, D. & de Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003)

    Article  ADS  CAS  Google Scholar 

  26. Celli, G. B., Lazzerini Denchi, E. & de Lange, T. Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nature Cell Biol. 8, 885–890 (2006)

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Lobrich, M. & Jeggo, P. A. Harmonising the response to DSBs: a new string in the ATM bow. DNA Repair (Amst.) 4, 749–759 (2005)

    Article  Google Scholar 

  29. Ye, J. Z. et al. POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev. 18, 1649–1654 (2004)

    Article  CAS  Google Scholar 

Download references


We thank D. White for invaluable help in maintaining our mouse colonies, D. Argibay for assistance with genotyping, E. Brown for providing the ATR conditional knockout mice, H. Takai for technical advice and suggestions, D. Hockemeyer for providing Pot1 double knockout cells and the Tpp1 and Pot1a shRNA constructs, S. Soll for his contributions to the initial stages of this research and members of the de Lange laboratory for critical comments on the manuscript. This work was supported by a grant from the NIH.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Titia de Lange.

Ethics declarations

Competing interests

Reprints and permissions information is available at The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S9 with Legends. Figures S1-S5 show γH2AX TIFs (S1), ChIP for shelterin (S2), ATR-independent DNA damage response (S3), ATM-dependent NEHJ (S4-S5) following TRF2 deletion. Figures S6-S7 show activation of ATR but not ATM upon POT1 inhibition. Figures S8-S9 show TIF formation and NHEJ in TRF2-/- ATM-/- cells upon POT1 inhibition. (PDF 1740 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Denchi, E., de Lange, T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448, 1068–1071 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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