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.

The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex


The MRE11 complex (MRE11, RAD50 and NBS1) and the ataxia-telangiectasia mutated (ATM) kinase function in the same DNA damage response pathway to effect cell cycle checkpoint activation and apoptosis1,2,3. The functional interaction between the MRE11 complex and ATM has been proposed to require a conserved C-terminal domain of NBS1 for recruitment of ATM to sites of DNA damage4,5. Human Nijmegen breakage syndrome (NBS) cells and those derived from multiple mouse models of NBS express a hypomorphic NBS1 allele that exhibits impaired ATM activity despite having an intact C-terminal domain3,6,7,8,9,10,11. This indicates that the NBS1 C terminus is not sufficient for ATM function. We derived Nbs1ΔC/ΔC mice in which the C-terminal ATM interaction domain is deleted. Nbs1ΔC/ΔC cells exhibit intra-S-phase checkpoint defects, but are otherwise indistinguishable from wild-type cells with respect to other checkpoint functions, ionizing radiation sensitivity and chromosome stability. However, multiple tissues of Nbs1ΔC/ΔC mice showed a severe apoptotic defect, comparable to that of ATM- or CHK2-deficient animals. Analysis of p53 transcriptional targets and ATM substrates showed that, in contrast to the phenotype of Chk2-/- mice, NBS1ΔC does not impair the induction of proapoptotic genes. Instead, the defects observed in Nbs1ΔC/ΔC result from impaired phosphorylation of ATM targets including SMC1 and the proapoptotic factor, BID.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Generation of Nbs1 ΔC/ΔC mice.
Figure 2: Cellular phenotypes of Nbs1ΔC/ΔC.
Figure 3: Apoptotic phenotypes of Nbs1ΔC/ΔC.
Figure 4: Apoptotic signalling in Nbs1ΔC/ΔC.


  1. Stracker, T. H., Theunissen, J. W., Morales, M. & Petrini, J. H. The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair 3, 845–854 (2004)

    CAS  Article  Google Scholar 

  2. Morales, M. et al. The Rad50S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev. 19, 3043–3054 (2005)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  4. You, Z., Chahwan, C., Bailis, J., Hunter, T. & Russell, P. ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol. Cell. Biol. 25, 5363–5379 (2005)

    CAS  Article  Google Scholar 

  5. Falck, J., Coates, J. & Jackson, S. P. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434, 605–611 (2005)

    ADS  CAS  Article  Google Scholar 

  6. Carney, J. P. et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93, 477–486 (1998)

    CAS  Article  Google Scholar 

  7. Maser, R. S., Zinkel, R. & Petrini, J. H. J. An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nature Genet. 27, 417–421 (2001)

    CAS  Article  Google Scholar 

  8. Maser, R. S. et al. The MRE11 complex and DNA replication: linkage to E2F and sites of DNA synthesis. Mol. Cell. Biol. 21, 6006–6016 (2001)

    CAS  Article  Google Scholar 

  9. Williams, B. R. et al. A murine model of Nijmegen breakage syndrome. Curr. Biol. 12, 648–653 (2002)

    CAS  Article  Google Scholar 

  10. Kang, J., Bronson, R. T. & Xu, Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J. 21, 1447–1455 (2002)

    CAS  Article  Google Scholar 

  11. Difilippantonio, S. et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nature Cell Biol. 7, 675–685 (2005)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  13. Xu, Y. & Baltimore, D. Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10, 2401–2410 (1996)

    CAS  Article  Google Scholar 

  14. Xu, Y. et al. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10, 2411–2422 (1996)

    CAS  Article  Google Scholar 

  15. Yamazaki, V., Wegner, R. D. & Kirchgessner, C. U. Characterization of cell cycle checkpoint responses after ionizing radiation in Nijmegen breakage syndrome cells. Cancer Res. 58, 2316–2322 (1998)

    CAS  PubMed  Google Scholar 

  16. Kang, J. et al. Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression. Mol. Cell. Biol. 25, 661–670 (2005)

    CAS  Article  Google Scholar 

  17. Kang, J., Bronson, R. & Xu, Y. Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair. EMBO J. 21, 1447–1455 (2002)

    CAS  Article  Google Scholar 

  18. Kitagawa, R., Bakkenist, C. J., McKinnon, P. J. & Kastan, M. B. Phosphorylation of SMC1 is a critical downstream event in the ATM–NBS1–BRCA1 pathway. Genes Dev. 18, 1423–1438 (2004)

    CAS  Article  Google Scholar 

  19. Bakkenist, C. J. & Kastan, M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499–506 (2003)

    ADS  CAS  Article  Google Scholar 

  20. Bender, C. F. et al. Cancer predisposition and hematopoietic failure in Rad50S/S mice. Genes Dev. 16, 2237–2251 (2002)

    CAS  Article  Google Scholar 

  21. Takai, H. et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21, 5195–5205 (2002)

    CAS  Article  Google Scholar 

  22. Hirao, A. et al. Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol. Cell. Biol. 22, 6521–6532 (2002)

    CAS  Article  Google Scholar 

  23. Falck, J., Petrini, J. H., Williams, B. R., Lukas, J. & Bartek, J. The DNA damage-dependent intra–S phase checkpoint is regulated by parallel pathways. Nature Genet. 30, 290–294 (2002)

    Article  Google Scholar 

  24. Kamer, I. et al. Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 122, 593–603 (2005)

    CAS  Article  Google Scholar 

  25. Zinkel, S. S. et al. A role for proapoptotic BID in the DNA-damage response. Cell 122, 579–591 (2005)

    CAS  Article  Google Scholar 

  26. Kastan, M. B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992)

    CAS  Article  Google Scholar 

  27. Lee, J. H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11–Rad50–Nbs1 complex. Science 308, 551–554 (2005)

    ADS  CAS  Article  Google Scholar 

  28. Theunissen, J. W. & Petrini, J. H. Methods for studying the cellular response to DNA damage: influence of the Mre11 complex on chromosome metabolism. Methods Enzymol. 409, 251–284 (2006)

    CAS  Article  Google Scholar 

  29. Theunissen, J. W. et al. Checkpoint failure and chromosomal instability without lymphomagenesis in Mre11ATLD1/ATLD1 mice. Mol. Cell 12, 1511–1523 (2003)

    CAS  Article  Google Scholar 

  30. Liu, P., Jenkins, N. A. & Copeland, N. G. A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res. 13, 476–484 (2003)

    CAS  Article  Google Scholar 

Download references


We thank N. Copeland, N. Jenkins, and C. Adelman for assistance with recombineering and ES cell culture, J. Theunissen for assistance with checkpoint and apoptotic analysis, G. Oltz and E. Rhuley for AC1 ES cells, Y. Shiloh for anti-ATM (MAT3) antibodies, and Petrini laboratory members for helpful suggestions. T.H.S. was supported by an NRSA fellowship and this work was supported by NIH grants awarded to J.H.P. and the Joel and Joan Smilow Initiative.

Author Contributions T.H.S. and J.H.P. conceived the experiments and wrote the paper. T.H.S., M.M., S.S.C., and H.H. performed the experiments.

Author information

Authors and Affiliations


Corresponding author

Correspondence to John H. J. Petrini.

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-S6 with Legends. (PDF 923 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stracker, T., Morales, M., Couto, S. et al. The carboxy terminus of NBS1 is required for induction of apoptosis by the MRE11 complex. Nature 447, 218–221 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


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