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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation

Author

Listed:
  • Christopher J. Bakkenist

    (St Jude Children's Research Hospital)

  • Michael B. Kastan

    (St Jude Children's Research Hospital)

Abstract

The ATM protein kinase, mutations of which are associated with the human disease ataxia–telangiectasia, mediates responses to ionizing radiation in mammalian cells. Here we show that ATM is held inactive in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine 1981 that is contained within the previously described ‘FAT’ domain. Cellular irradiation induces rapid intermolecular autophosphorylation of serine 1981 that causes dimer dissociation and initiates cellular ATM kinase activity. Most ATM molecules in the cell are rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody is detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation, and our data indicate that ATM activation is not dependent on direct binding to DNA strand breaks, but may result from changes in the structure of chromatin.

Suggested Citation

  • Christopher J. Bakkenist & Michael B. Kastan, 2003. "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation," Nature, Nature, vol. 421(6922), pages 499-506, January.
    • Handle: RePEc:nat:nature:v:421:y:2003:i:6922:d:10.1038_nature01368
    DOI: 10.1038/nature01368
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    Citations

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    Cited by:

    1. Huimin Zhang & Yun Xiong & Dan Su & Chao Wang & Mrinal Srivastava & Mengfan Tang & Xu Feng & Min Huang & Zhen Chen & Junjie Chen, 2022. "TDP1-independent pathways in the process and repair of TOP1-induced DNA damage," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Zhang, L.W. & Cheng, Y.M. & Liew, K.M., 2014. "Mathematical modeling of p53 pulses in G2 phase with DNA damage," Applied Mathematics and Computation, Elsevier, vol. 232(C), pages 1000-1010.
    3. Salvatore Terrazzino & Sarah Cargnin & Letizia Deantonio & Carla Pisani & Laura Masini & Pier Luigi Canonico & Armando A Genazzani & Marco Krengli, 2019. "Impact of ATM rs1801516 on late skin reactions of radiotherapy for breast cancer: Evidences from a cohort study and a trial sequential meta-analysis," PLOS ONE, Public Library of Science, vol. 14(11), pages 1-21, November.
    4. Rut Molinuevo & Julien Menendez & Kora Cadle & Nabeela Ariqat & Marie Klaire Choy & Cayla Lagousis & Gwen Thomas & Catherine Strietzel & J. W. Bubolz & Lindsay Hinck, 2024. "Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    6. Sylvain V Costes & Artem Ponomarev & James L Chen & David Nguyen & Francis A Cucinotta & Mary Helen Barcellos-Hoff, 2007. "Image-Based Modeling Reveals Dynamic Redistribution of DNA Damage into Nuclear Sub-Domains," PLOS Computational Biology, Public Library of Science, vol. 3(8), pages 1-12, August.

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