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.

  • Review Article
  • Published:

The many substrates and functions of ATM

Nature Reviews Molecular Cell Biology volume 1, pages 179–186 (2000)Cite this article

Abstract

As its name suggests, the ATM ? 'ataxia-telangiectasia, mutated' ? gene is responsible for the rare disorder ataxia-telangiectasia. Patients show various abnormalities, mainly in their responses to DNA damage, but also in other cellular processes. Although it is hard to understand how a single gene product is involved in so many physiological processes, a clear picture is starting to emerge.

Key Points

online summary

  • Ataxia-telangiectasia, mutated (ATM) is the gene responsible for the rare disorder ataxia-telangiectasia. Patients show abnormalities mainly in their response to DNA damage.

  • ATM acts specifically in the cellular response to ionizing radiation and DNA double-stranded breaks (DSBs).

  • ATM differs from other similar DNA-repair enzymes (ATR and DNA-PK) in that its activity does not depend on manganese and, unlike DNA-PK, it is not clear that the activity of ATM is directly activated by DNA ends.

  • The cell-cycle checkpoint responses at G1, S and G2 are all markedly abnormal in ATM-deficient cells.

  • ATM is proposed to regulate the G1 checkpoint through indirect regulation of p53. Evidence indicates that ATM phosphorylates another kinase CHK2, which in turn phosphorylates p53. This disrupts the interaction between p53 and MDM2, and so induces a G1 checkpoint.

  • ATM controls the S-phase checkpoint through phosphorylation of NBS1, which localizes in a complex that is recruited to DSBs. Other proteins in this complex are also possible targets.

  • None of the proteins that regulates the G2?M checkpoint has been identified as an ATM target. Evidence is discussed in support of coordination between two candidates ? CHK1 and CHK2 ? which are phosphorylated by ATR and ATM, respectively. BRCA1, which is phosphorylated by both ATM and CHK2, is also implicated.

  • ATM-deficient cells show abnormal DSB repair. This may be due to abnormal chromatin remodelling; this is supported by the observation that ATM binds to the chromatin-remodelling enzyme histone deacetylase. ATM is also required for homologous recombination, one of the pathways that functions to repair DSBs.

  • Patients with ataxia telangiectasia also have abnormal nervous-system development and insulin signalling. It is not clear whether the defects observed in these patients are due just to a loss of DSB repair in these tissues or whether ATM functions in other signalling pathways here.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Function of ATM in cell-cycle checkpoints and DNA repair pathways.
Figure 2: ATM and other molecular signals controlling cell-cycle checkpoints after ionizing radiation.
Figure 3: A role of ATM in DNA double-stranded break repair pathways.

Similar content being viewed by others

References

  1. Savitsky, K. et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268, 1749? 1753 (1995).The report of the cloning of the ATM gene after a two-decade search.

    Article  CAS  PubMed  Google Scholar 

  2. Hunter, T. When is a lipid kinase not a lipid kinase? When it is a protein kinase. Cell 83, 1?4 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  3. Lavin, M. F. & Shiloh, Y. The genetic defect in ataxia-telangiectasia . Annu. Rev. Immunol. 15, 177? 202 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Smith, G. C. & Jackson, S. P. The DNA-dependent protein kinase . Genes Dev. 13, 916?934 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Abraham, R. T. Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr. Opin. Immunol. 10, 330?336 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677? 1679 (1998).

    Article  CAS  PubMed  Google Scholar 

  7. Banin, S. et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage . Science 281, 1674?1677 (1998).References 6 and 7 reported that ATM directly phosphorylates p53 and is activated by DNA damage.

    Article  CAS  PubMed  Google Scholar 

  8. Kim, S. T., Lim, D. S., Canman, C. E. & Kastan, M. B. Substrate specificities and identification of putative substrates of ATM kinase family members. J. Biol. Chem. 274, 37538 ?37543 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Chan, D. W. et al. Purification and characterization of ATM from human placenta. A manganese-dependent, wortmannin-sensitive serine/threonine protein kinase . J. Biol. Chem. 275, 7803? 7810 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Dhand, R. et al. PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 13 , 522?533 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith, G. C. et al. Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM. Proc. Natl Acad. Sci. USA 96, 11134?11139 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gately, D. P., Hittle, J. C., Chan, G. K. & Yen, T. J. Characterization of ATM expression, localization, and associated DNA-dependent protein kinase activity. Mol. Biol. Cell 9, 2361?2374 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Barlow, C. et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86, 15?71 ( 1996).The generation of the first ataxia-telangiectasia-knockout mouse with many, but not all, of the features of the human disease.

    Article  Google Scholar 

  15. Brown, E. J. & Baltimore, D. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14, 397?402 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Komatsu, K., Yoshida, M. & Okumura, Y. Murine scid cells complement ataxia-telangiectasia cells and show a normal post-irradiation response of DNA synthesis. Int. J. Radiat. Biol. 63, 725?730 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Huang, L. C., Clarkin, K. C. & Wahl, G. M. p53-dependent cell cycle arrests are preserved in DNA-activated protein kinase-deficient mouse fibroblasts. Cancer Res. 56, 2940?2944 ( 1996).

    CAS  PubMed  Google Scholar 

  18. Allalunis-Turner, J., Barron, G. M. & Day, R. S. Intact G2-phase checkpoint in cells of a human cell line lacking DNA-dependent protein kinase activity. Radiat. Res. 147, 284?287 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  19. 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). The first linkage of the ataxia-telangiectasia gene product with the p53 pathway.

    Article  CAS  PubMed  Google Scholar 

  20. Houldsworth, J. & Lavin, M. F. Effect of ionizing radiation on DNA synthesis in ataxia telangiectasia cells. Nucleic Acids Res. 8, 3709?3720 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Painter, R. B. & Young, B. R. Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc. Natl Acad. Sci. USA 77, 7315?7317 ( 1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Beamish, H. & Lavin, M. F. Radiosensitivity in ataxia-telangiectasia: anomalies in radiation-induced cell cycle delay. Int. J. Radiat. Biol. 65, 175?184 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  23. O'Neill, T. et al. Utilization of oriented peptide libraries to identify substrate motifs selected by ATM. J. Biol. Chem. 275, 22719?22727 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Morgan, S. E. & Kastan, M. B. p53 and ATM: cell cycle, cell death, and cancer. Adv. Cancer Res. 71, 1?25 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51 , 6304?6311 (1991).

    CAS  PubMed  Google Scholar 

  26. Giaccia, A. J. & Kastan, M. B. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12, 2973?2983 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  27. el-Deiry, W. S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817?825 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  28. Shieh, S. Y., Ikeda, M., Taya, Y. & Prives, C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325?334 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Siliciano, J. D. et al. DNA damage induces phosphorylation of the amino terminus of p53. Genes Dev. 11, 3471? 3481 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ashcroft, M., Kubbutat, M. H. & Vousden, K. H. Regulation of p53 function and stability by phosphorylation . Mol. Cell. Biol. 19, 1751? 1758 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chehab, N. H., Malikzay, A., Stavridi, E. S. & Halazonetis, T. D. Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 13777?13782 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dumaz, N. & Meek, D. W. Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2 . EMBO J. 18, 7002?7010 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sakaguchi, K. et al. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 12, 2831? 2841 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Haupt, Y., Maya, R., Kazaz, A. & Oren, M. Mdm2 promotes the rapid degradation of p53. Nature 387, 296 ?299 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Kubbutat, M. H., Jones, S. N. & Vousden, K. H. Regulation of p53 stability by Mdm2. Nature 387, 299?303 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  36. Khosravi, R. et al. Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage. Proc. Natl Acad. Sci. USA 96, 14973?14977 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Maya, R. et al. ATM-dependent phosphorylation of Mdm2 on serine 394: role in p53 activation by DNA damage. Genes Dev. (submitted).

  38. Shieh, S. Y., Taya, Y. & Prives, C. DNA damage-inducible phosphorylation of p53 at N-terminal sites including a novel site, Ser20, requires tetramerization. EMBO J. 18, 1815?1823 ( 1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hirao, A. et al. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287, 1824? 1827 (2000).Development of Chk2-knockout mouse cells and linkage of Chk2 to p53 and the G1-checkpoint pathway.

    Article  CAS  PubMed  Google Scholar 

  40. Chehab, N. H., Malikzay, A., Appel, M. & Halazonetis, T. D. Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev. 14, 278?288 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shieh, S. Y., Ahn, J., Tamai, K., Taya, Y. & Prives, C. The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev. 14, 289?300 ( 2000).References 40 and 41 show that CHK2 phosphorylates p53 on serine 20 and contributes to its stabilization in an ATM-dependent manner.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Matsuoka, S., Huang, M. & Elledge, S. J. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282, 1893? 1897 (1998).Demonstration that CHK2 is phosphorylated and regulated by ATM.

    Article  CAS  PubMed  Google Scholar 

  43. Zhou, B. B. et al. Caffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity. J. Biol. Chem. 275, 10342?10348 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Slebos, R. J. et al. p53-dependent G1 arrest involves pRB-related proteins and is disrupted by the human papillomavirus 16 E7 oncoprotein. Proc. Natl Acad. Sci. USA 91, 5320?5324 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Di Leonardo, A., Linke, S. P., Clarkin, K. & Wahl, G. M. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 8, 2540?2551 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Larner, J. M., Lee, H. & Hamlin, J. L. Radiation effects on DNA synthesis in a defined chromosomal replicon. Mol. Cell. Biol. 14, 1901? 1908 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Morgan, S. E., Lovly, C., Pandita, T. K., Shiloh, Y. & Kastan, M. B. Fragments of ATM which have dominant-negative or complementing activity. Mol. Cell. Biol. 17, 2020?2029 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shiloh, Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31, 635 ?662 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Varon, R. et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93, 467?476 (1998).References 49 and 50 reported the cloning of the NBS1 gene and demonstrated its interactions with MRE11 and RAD50.

    Article  CAS  PubMed  Google Scholar 

  51. Paull, T. T. & Gellert, M. Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes Dev. 13, 1276?1288 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lim, D. S. et al. ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway . Nature 404, 613?617 (2000).Demonstration that ATM activation is not dependent on NBS1, but rather that ATM phosphorylates NBS1 and that this phosphorylation is important for the ionizing-radiation-induced S-phase checkpoint.

    Article  CAS  PubMed  Google Scholar 

  53. Gatei, M. et al. ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genet. 25, 115? 119 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Zhao, S. et al. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405, 473? 477 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Wu, X. et al. ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405, 477 ?482 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Stewart, G. S. et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577?587 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  57. Zhong, Q. et al. Association of BRCA1 with the hRad50?hMre11?p95 complex and the DNA damage response. Science 285, 747?750 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927?939 ( 2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Paulovich, A. G. & Hartwell, L. H. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 82, 841? 847 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Lindsay, H. D. et al. S-phase-specific activation of Cds1 kinase defines a subpathway of the checkpoint response in Schizosaccharomyces pombe. Genes Dev. 12, 382?395 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Elledge, S. J. Cell cycle checkpoints: preventing an identity crisis. Science 274, 1664?1672 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  62. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162? 1166 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Scott, D., Spreadborough, A. R. & Roberts, S. A. Radiation-induced G2 delay and spontaneous chromosome aberrations in ataxia-telangiectasia homozygotes and heterozygotes. Int. J. Radiat. Biol. 66, S157?S163 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Peng, C. Y. et al. Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277, 1501?1505 (1997). Demonstration of a G2-checkpoint control mechanism involving 14-3-3 protein binding regulated by phosphorylation of CDC25C.

    Article  CAS  PubMed  Google Scholar 

  65. Liu, Q. et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 14 , 1448?1459 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Takai, H. et al. Aberrant cell cycle checkpoint function and early embryonic death in Chk1(−/−) mice. Genes Dev. 14, 1439?1447 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Rhind, N. & Russell, P. Mitotic DNA damage and replication checkpoints in yeast. Curr. Opin. Cell Biol. 10, 749?758 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Walworth, N. C. & Bernards, R. Rad-dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint. Science 271, 353?356 ( 1996).

    Article  CAS  PubMed  Google Scholar 

  69. Sanchez, Y. et al. Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science 286, 1166?1171 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Sanchez, Y. et al. Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271 , 357?360 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Xu, X. et al. Centrosome amplification and a defective G2?M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells . Mol. Cell 3, 389?395 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Verhaegh, G. W. et al. A gene that regulates DNA replication in response to DNA damage is located on human chromosome 4q. Am. J. Hum. Genet. 57, 1095?1103 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. McKinnon, P. J. Ataxia-telangiectasia: an inherited disorder of ionizing-radiation sensitivity in man. Progress in the elucidation of the underlying biochemical defect. Hum. Genet. 75, 197?208 (1987).

    Article  CAS  PubMed  Google Scholar 

  74. Cornforth, M. N. & Bedford, J. S. On the nature of a defect in cells from individuals with ataxia-telangiectasia. Science 227, 1589?1591 ( 1985).

    Article  CAS  PubMed  Google Scholar 

  75. Pandita, T. K. & Hittelman, W. N. Initial chromosome damage but not DNA damage is greater in ataxia telangiectasia cells. Radiat. Res. 130, 94?103 (1992).

    Article  CAS  PubMed  Google Scholar 

  76. Guo, C. Y., Wang, Y., Brautigan, D. L. & Larner, J. M. Histone H1 dephosphorylation is mediated through a radiation-induced signal transduction pathway dependent on ATM. J. Biol. Chem. 274, 18715?18720 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Kim, G. D. et al. Sensing of ionizing radiation-induced DNA damage by ATM through interaction with histone deacetylase. J. Biol. Chem. 274, 31127?31130 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Karran, P. DNA double strand break repair in mammalian cells. Curr. Opin. Genet. Dev. 10, 144?150 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Meyn, M. S. High spontaneous intrachromosomal recombination rates in ataxia- telangiectasia . Science 260, 1327?1330 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Bishop, A. J., Barlow, C., Wynshaw-Boris, A. J. & Schiestl, R. H. Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice. Cancer Res. 60, 395 ?399 (2000).

    CAS  PubMed  Google Scholar 

  81. Luo, C. M. et al. High frequency and error-prone DNA recombination in ataxia telangiectasia cell lines. J. Biol. Chem. 271, 4497?4503 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Chen, G. et al. Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl. J. Biol. Chem. 274, 12748?12752 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Morrison, C. et al. The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J. 19, 463? 471 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells . Cell 88, 265?275 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Gowen, L. C., Avrutskaya, A. V., Latour, A. M., Koller, B. H. & Leadon, S. A. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281, 1009?1012 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511?518 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Lee, J. S., Collins, K. M., Brown, A. L., Lee, C. H. & Chung, J. H. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404, 201?204 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Li, S. et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage responses. Nature 406, 210 ?215 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Stewart, G. S. et al. The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99, 577?587 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  90. Ivanov, E. L., Korolev, V. G. & Fabre, F. XRS2, a DNA repair gene of Saccharomyces cerevisiae , is needed for meiotic recombination. Genetics 132, 651?664 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ajimura, M., Leem, S. H. & Ogawa, H. Identification of new genes required for meiotic recombination in Saccharomyces cerevisiae. Genetics 133, 51?66 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lee, Y., Barnes, D. E., Lindahl, T. & McKinnon, P. J. Defective neurogenesis resulting from DNA ligase IV deficiency requires ATM . Genes Dev. 14, 2576?2550 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Baskaran, R. et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387 , 516?519 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Lee, S. J., Dimtchev, A., Lavin, M. F., Dritschilo, A. & Jung, M. A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-κB. Oncogene 17, 1821?1826 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  95. Lim, D. S. et al. ATM binds to β-adaptin in cytoplasmic vesicles. Proc. Natl Acad. Sci. USA 95, 10146? 10151 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Oka, A. & Takashima, S. Expression of the ataxia-telangiectasia gene (ATM) product in human cerebellar neurons during development. Neurosci. Lett. 252, 195?198 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Barlow, C. et al. ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation. Proc. Natl Acad. Sci. USA 97 , 871?876 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yang, D. & Kastan, M. B. Participation of ATM in insulin signalling through phosphorylation of eIF-4E binding protein 1 (4E?BP1) . Nature Cell Biol. 2, 893? 898 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Meijer, M. & Smerdon, M. J. Accessing DNA damage in chromatin: insights from transcription. Bioessays 21, 596?603 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Gatti, R. A. et al. Genetic haplotyping of ataxia-telangiectasia families localizes the major gene to an approximately 850 kb region on chromosome 11q23. 1. Int. J. Radiat. Biol. 66, S57?S62 (1994).

    CAS  PubMed  Google Scholar 

  101. Tibbetts, R. S. et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 13, 152? 157 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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  PubMed  Google Scholar 

  103. Hari, K. L. et al. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 82, 815?821 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  104. Cimprich, K. A., Shin, T. B., Keith, C. T. & Schreiber, S. L. cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein . Proc. Natl Acad. Sci. USA 93, 2850? 2855 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Cliby, W. A. et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 17, 159?169 ( 1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Matsuoka, S. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc. Natl Acad. Sci. USA 97, 10389?10394 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ahn, J.-Y., Schwarz, J. K., Piwnica?Worms, H. & Canman, C. E. Threonine 68 phosphorylation by ATM is required for efficient activation of Chk2 in response to ionizing radiation. Cancer Res. (in the press).

  108. Gatei, M. et al. Role for ATM in DNA damage-induced phosphorylation of BRCA1 . Cancer Res. 15, 3299? 3304 (2000). [ PubMed]

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology?Oncology, Saint Jude Children's Research Hospital, D1034, 332 North Lauderdale Street , Memphis, 38105, Tennessee, USA

    Michael B. Kastan & Dae-sik Lim

Authors
  1. Michael B. Kastan
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Dae-sik Lim
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Michael B. Kastan.

Supplementary information

Related links

Related links

DATABASE LINKS

Ataxia-telangiectasia

ATM

PI(3)K

MTOR

DNA-PK

p53

KU70

KU80

RPA

ATR

p21

CDK2

p300

MDM2

CHK2

NBS1

Nijmegen breakage syndrome

RAD50

MRE11

ataxia-telangiectasia-like disorder

BRCA1

CDC25

CHK1

MSH2

MSH6

MLH

BLM

ligase IV

c-Abl

NF-κB

β-adaptin

4E-BP1

Glossary

REPLICATION PROTEIN A

A single-stranded DNA-binding factor that is essential for DNA repair, recombination and replication.

V(D)J RECOMBINATION

A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. DNA double-strand breaks are introduced between the V, D and J segments and DNA repair proteins then join the segments together.

CHK2

A serine/threonine protein kinase that has an important function in cell-cycle regulation in response to DNA damage.

RADIORESISTANT DNA SYNTHESIS

A failure of the rapid decrease in DNA synthesis in ataxia-telangiectasia cells that occurs in normal cells after ionizing radiation.

RESTRICTION POINT

A point late in the G1 stage of the cell cycle at which mammalian cells become committed to entry into S phase, even without other growth factors.

REPLICON

A structural complex at which replication of DNA occurs.

HYDROXYUREA

A inhibitor of ribonucleotide reductase that blocks replication during S phase by preventing nucleotide synthesis.

MICROCEPHALY

An abnormally small head.

ATAXIA

Dyscoordination of gait and other movements controlled by cerebellum.

BRCA1

A tumour-suppressor gene that is linked to hereditary early onset of breast and ovarian cancer.

PROPIDIUM IODIDE ASSAY

A fluorescent DNA-intercalating dye used to measure DNA content in flow cytometry assays.

14-3-3 PROTEIN

A regulatory protein that binds to phosphorylated forms of various proteins that are involved in signal transduction and cell-cycle control.

BLASTOCYST

An early stage of embryonic development at which cells begin to commit to certain developmental lineages.

HISTONE DEACETYLASE

An enzyme that removes the acetyl groups of core histones; its activity has an important function in transcriptional regulation and cell-cycle progression through alterations in chromatin structure.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kastan, M., Lim, Ds. The many substrates and functions of ATM. Nat Rev Mol Cell Biol 1, 179–186 (2000). https://doi.org/10.1038/35043058

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35043058

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