Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors.
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.
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.|Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States.
Kenta
K
Yamamoto
Department of Biomedical Informatics, Columbia University, New York, United States.|Department of Systems Biology, Columbia University, New York, United States.|College of Physicians & Surgeons, Columbia University, New York, United States.
Jiguang
J
Wang
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.|Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States.
Lisa
L
Sprinzen
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States.
Jun
J
Xu
Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States.
Christopher J
CJ
Haddock
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.
Chen
C
Li
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.
Brian J
BJ
Lee
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.
Denis G
DG
Loredan
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.
Wenxia
W
Jiang
Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States.
Alessandro
A
Vindigni
Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States.
Dong
D
Wang
Department of Biomedical Informatics, Columbia University, New York, United States.|Department of Systems Biology, Columbia University, New York, United States.|College of Physicians & Surgeons, Columbia University, New York, United States.
Raul
R
Rabadan
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.|Department of Pathology and Cell Biology, Columbia University, New York, United States.|College of Physicians and Surgeons, Columbia University, New York, United States.|Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Columbia University, New York, United States.|Department of Pediatrics, Columbia University, New York, United States.|College of Physicians & Surgeons, Columbia University, New York, United States.
Shan
0000-0002-6568-1818
S
Zha
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D063646:Carcinogenesis; D004195:Disease Models, Animal; D008223:Lymphoma / Q000188:drug therapy / Q000503:physiopathology; D051379:Mice; D059004:Topoisomerase I Inhibitors / Q000378:metabolism*
D059004:Topoisomerase I Inhibitors; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
ATM; Topo-isomerase I; cell biology; human; missense mutation; mouse; replication fork