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Elife. 2016 Jun 15;5. pii: e14709. doi: 10.7554/eLife.14709.

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

Yamamoto K1,2,3,4, Wang J5,6,7, Sprinzen L1,2,3,4, Xu J8, Haddock CJ9, Li C1,2,3, Lee BJ1,2,3, Loredan DG1,2,3, Jiang W1,2,3, Vindigni A9, Wang D8, Rabadan R5,6,7, Zha S1,2,3,10,11,7.

Author information

1
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.
2
Department of Pathology and Cell Biology, Columbia University, New York, United States.
3
College of Physicians and Surgeons, Columbia University, New York, United States.
4
Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States.
5
Department of Biomedical Informatics, Columbia University, New York, United States.
6
Department of Systems Biology, Columbia University, New York, United States.
7
College of Physicians & Surgeons, Columbia University, New York, United States.
8
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States.
9
Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States.
10
Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Columbia University, New York, United States.
11
Department of Pediatrics, Columbia University, New York, 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 (Atm(KD/-)) 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 Atm(KD/-), but not Atm-proficientor 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.

KEYWORDS:

ATM; Topo-isomerase I; cell biology; human; missense mutation; mouse; replication fork

PMID:
27304073
PMCID:
PMC4957979
DOI:
10.7554/eLife.14709
[Indexed for MEDLINE]
Free PMC Article

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