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

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)

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.

Metrics

  • 4,082
    views
  • 734
    downloads
  • 43
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2016)
Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors
eLife 5:e14709.
https://doi.org/10.7554/eLife.14709

Share this article

https://doi.org/10.7554/eLife.14709

Further reading

    1. Cancer Biology
    2. Cell Biology
    Brooke A Conti, Leo Novikov ... Mariano Oppikofer
    Research Article

    DNA base lesions, such as incorporation of uracil into DNA or base mismatches, can be mutagenic and toxic to replicating cells. To discover factors in repair of genomic uracil, we performed a CRISPR knockout screen in the presence of floxuridine, a chemotherapeutic agent that incorporates uracil and fluorouracil into DNA. We identified known factors, such as uracil DNA N-glycosylase (UNG), and unknown factors, such as the N6-adenosine methyltransferase, METTL3, as required to overcome floxuridine-driven cytotoxicity. Visualized with immunofluorescence, the product of METTL3 activity, N6-methyladenosine, formed nuclear foci in cells treated with floxuridine. The observed N6-methyladenosine was embedded in DNA, called 6mA, and these results were confirmed using an orthogonal approach, liquid chromatography coupled to tandem mass spectrometry. METTL3 and 6mA were required for repair of lesions driven by additional base-damaging agents, including raltitrexed, gemcitabine, and hydroxyurea. Our results establish a role for METTL3 and 6mA in promoting genome stability in mammalian cells, especially in response to base damage.

    1. Cancer Biology
    Pierluigi Scerbo, Benjamin Tisserand ... Bertrand Ducos
    Research Article

    Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.