ATM stabilizes DNA double-strand-break complexes during V(D)J recombination (original) (raw)

Nature volume 442, pages 466–470 (2006)Cite this article

Abstract

The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents1,2,3,4. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving lymphocyte antigen receptor loci5,6. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs1,2,3,4. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during lymphocyte antigen receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving antigen receptor loci associated with ataxia-telangiectasia.

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References

  1. Kastan, M. B. & Lim, D. S. The many substrates and functions of ATM. Nature Rev. Mol. Cell Biol. 1, 179–186 (2000)
    Article CAS Google Scholar
  2. Pandita, T. K. A multifaceted role for ATM in genome maintenance. Expert Rev. Mol. Med. 5, 1–21 (2003)
    Article PubMed Google Scholar
  3. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003)
    Article CAS Google Scholar
  4. Durocher, D. & Jackson, S. P. DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme? Curr. Opin. Cell Biol. 13, 225–231 (2001)
    Article CAS PubMed Google Scholar
  5. Lavin, M. F. & Shiloh, Y. The genetic defect in ataxia-telangiectasia. Annu. Rev. Immunol. 15, 177–202 (1997)
    Article CAS PubMed Google Scholar
  6. Taylor, A. M., Metcalfe, J. A., Thick, J. & Mak, Y. F. Leukemia and lymphoma in ataxia telangiectasia. Blood 87, 423–438 (1996)
    CAS PubMed Google Scholar
  7. Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983)
    Article ADS CAS PubMed Google Scholar
  8. Fugmann, S. D., Lee, A. I., Shockett, P. E., Villey, I. J. & Schatz, D. G. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18, 495–527 (2000)
    Article CAS PubMed Google Scholar
  9. Oettinger, M. A. V(D)J recombination: on the cutting edge. Curr. Opin. Cell Biol. 11, 325–329 (1999)
    Article CAS PubMed Google Scholar
  10. Gellert, M. V(D)J recombination: rag proteins, repair factors, and regulation. Annu. Rev. Biochem. 71, 101–132 (2002)
    Article CAS PubMed Google Scholar
  11. Bassing, C. H. & Alt, F. W. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst.) 3, 781–796 (2004)
    Article CAS Google Scholar
  12. Matei, I. R., Guidos, C. J. & Danska, J. S. ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection. Immunol. Rev. 209, 142–158 (2006)
    Article CAS PubMed Google Scholar
  13. Perkins, E. J. et al. Sensing of intermediates in V(D)J recombination by ATM. Genes Dev. 16, 159–164 (2002)
    Article CAS PubMed PubMed Central Google Scholar
  14. Liao, M. J. & Van Dyke, T. Critical role for Atm in suppressing V(D)J recombination-driven thymic lymphoma. Genes Dev. 13, 1246–1250 (1999)
    Article CAS PubMed PubMed Central Google Scholar
  15. Petiniot, L. K. et al. Recombinase-activating gene (RAG) 2-mediated V(D)J recombination is not essential for tumorigenesis in Atm-deficient mice. Proc. Natl Acad. Sci. USA 97, 6664–6669 (2000)
    Article ADS CAS PubMed PubMed Central Google Scholar
  16. Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992)
    Article ADS CAS PubMed Google Scholar
  17. 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)
    Article CAS PubMed PubMed Central Google Scholar
  18. Muljo, S. A. & Schlissel, M. S. A small molecule Abl kinase inhibitor induces differentiation of Abelson virus-transformed pre-B cell lines. Nature Immunol. 4, 31–37 (2003)
    Article CAS Google Scholar
  19. Liang, H. E. et al. The “dispensable” portion of RAG2 is necessary for efficient V-to-DJ rearrangement during B and T cell development. Immunity 17, 639–651 (2002)
    Article CAS PubMed Google Scholar
  20. Lewis, S. M., Hesse, J. E., Mizuuchi, K. & Gellert, M. Novel strand exchanges in V(D)J recombination. Cell 55, 1099–1107 (1988)
    Article CAS PubMed Google Scholar
  21. Morzycka-Wroblewska, E., Lee, F. E. & Desiderio, S. V. Unusual immunoglobulin gene rearrangement leads to replacement of recombinational signal sequences. Science 242, 261–263 (1988)
    Article ADS CAS PubMed Google Scholar
  22. Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004)
    Article CAS PubMed Google Scholar
  23. Roth, D. B., Menetski, J. P., Nakajima, P. B., Bosma, M. J. & Gellert, M. V(D)J recombination: broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell 70, 983–991 (1992)
    Article CAS PubMed Google Scholar
  24. Franco, S. et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21, 201–214 (2006)
    Article CAS PubMed Google Scholar
  25. Agrawal, A. & Schatz, D. G. RAG1 and RAG2 form a stable postcleavage synaptic complex with DNA containing signal ends in V(D)J recombination. Cell 89, 43–53 (1997)
    Article CAS PubMed Google Scholar
  26. Hiom, K. & Gellert, M. Assembly of a 12/23 paired signal complex: a critical control point in V(D)J recombination. Mol. Cell 1, 1011–1019 (1998)
    Article CAS PubMed Google Scholar
  27. Riballo, E. et al. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to _γ_-H2AX foci. Mol. Cell 16, 715–724 (2004)
    Article CAS PubMed Google Scholar
  28. Sekiguchi, J. A., Whitlow, S. & Alt, F. W. Increased accumulation of hybrid V(D)J joins in cells expressing truncated versus full-length RAGs. Mol. Cell 8, 1383–1390 (2001)
    Article CAS PubMed Google Scholar
  29. 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 PubMed Google Scholar

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Acknowledgements

We thank M. Schlissel for pMX-RSS-GFP/IRES-hCD4. STI571 was provided by Novartis Pharmaceuticals and KU-55933 was provided by G. Smith at KuDOS Pharmaceuticals. We thank H. Virgin, K. Murphy and M. Krangel for critical review of the manuscript. This work is supported in part by grants from the National Institutes of Health (to B.P.S. and T.K.P.) and the Department of Army (T.K.P.). C.H.B. is a Pew Scholar in the Biomedical Sciences and a recipient of a Pilot Project Award from the American Cancer Society. B.P.S. is a recipient of a Research Scholar Award from the American Cancer Society. C.-Y.H. is supported by a post-doctoral training grant and A.L.B. a pre-doctoral training grant from the NIH.

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, 63110, USA
    Andrea L. Bredemeyer, Ching-Yu Huang, Beth A. Helmink, Laura M. Walker, Katrina C. Khor & Barry P. Sleckman
  2. Department of Radiation Oncology, Washington University School of Medicine, St Louis, Missouri, 63110, USA
    Girdhar G. Sharma & Tej K. Pandita
  3. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA
    Beth Nuskey & Craig H. Bassing
  4. Division of Allergy and Immunology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA
    Kathleen E. Sullivan
  5. Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania, 19104, USA
    Craig H. Bassing

Authors

  1. Andrea L. Bredemeyer
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  2. Girdhar G. Sharma
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  3. Ching-Yu Huang
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  4. Beth A. Helmink
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  5. Laura M. Walker
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  6. Katrina C. Khor
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  7. Beth Nuskey
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  8. Kathleen E. Sullivan
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  9. Tej K. Pandita
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  10. Craig H. Bassing
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  11. Barry P. Sleckman
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Correspondence toBarry P. Sleckman.

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Supplementary Notes

This file contains Supplementary Figures 1–19, Supplementary Methods and Supplementary Notes. The Supplementary Figures show the setup of the experimental system, data from additional cell lines, and controls for Figures 1-4. (PDF 2604 kb)

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Bredemeyer, A., Sharma, G., Huang, CY. et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination.Nature 442, 466–470 (2006). https://doi.org/10.1038/nature04866

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