1. Cancer Biology
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Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors

  1. Kenta Yamamoto
  2. Jiguang Wang
  3. Lisa Sprinzen
  4. Jun Xu
  5. Christopher J Haddock
  6. Chen Li
  7. Brian J Lee
  8. Denis G Loredan
  9. Wenxia Jiang
  10. Alessandro Vindigni
  11. Dong Wang
  12. Raul Rabadan
  13. Shan Zha  Is a corresponding author
  1. Columbia Unviersity, United States
  2. University of California San Diego, United States
  3. Saint Louis University School of Medicine, United States
  4. Columbia University, United States
Research Article
  • Cited 24
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Cite this article as: eLife 2016;5:e14709 doi: 10.7554/eLife.14709

Abstract

Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficient or Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.

Article and author information

Author details

  1. Kenta Yamamoto

    Insitute for Cancer Genetics, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jiguang Wang

    Department of Biomedical Informatics and Department of Systems Biology, , College of Physicians & Surgeons, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lisa Sprinzen

    Insitute for Cancer Genetics, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jun Xu

    Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christopher J Haddock

    Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Chen Li

    Insitute for Cancer Genetics, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brian J Lee

    Insitute for Cancer Genetics, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Denis G Loredan

    Insitute for Cancer Genetics, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Wenxia Jiang

    Institute for Cancer Genetics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alessandro Vindigni

    Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Dong Wang

    Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Raul Rabadan

    Department of Biomedical Informatics and Department of Systems Biology, College of Physicians & Surgeons, Columbia Unviersity, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Shan Zha

    Institute for Cancer Genetics, Columbia University, New York, United States
    For correspondence
    sz2296@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All the animal work was approved by and performed according to the regulations of the Institutional Animal Care and Use Committee (IACUC) of Columbia University (protocol no AAAF7653, AAAD6250, AAAJ3651)

Reviewing Editor

  1. Johannes Walter, Harvard Medical School, United States

Publication history

  1. Received: January 26, 2016
  2. Accepted: June 14, 2016
  3. Accepted Manuscript published: June 15, 2016 (version 1)
  4. Version of Record published: July 22, 2016 (version 2)

Copyright

© 2016, Yamamoto et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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