Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors
- Columbia Unviersity, United States
- University of California San Diego, United States
- Saint Louis University School of Medicine, United States
- 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.
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Author details
Reviewing Editor
- Johannes Walter, Harvard Medical School, United States
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)
Version history
- Received: January 26, 2016
- Accepted: June 14, 2016
- Accepted Manuscript published: June 15, 2016 (version 1)
- 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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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
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