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

Kenta Yamamoto, Jiguang Wang, Lisa Sprinzen, Jun Xu, Christopher J. Haddock, Chen Li, Brian J. Lee, Denis G. Loredan, Wenxia Jiang, Alessandro Vindigni, Dong Wang, Raul Rabadan, Shan Zha

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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 (Atmnull), 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-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topoisomerase I inhibitor based therapy.

Original languageEnglish
Article numbere14709
JournaleLife
Volume5
Issue numberJUN2016
DOIs
StatePublished - Jun 15 2016
Externally publishedYes

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    Yamamoto, K., Wang, J., Sprinzen, L., Xu, J., Haddock, C. J., Li, C., Lee, B. J., Loredan, D. G., Jiang, W., Vindigni, A., Wang, D., Rabadan, R., & Zha, S. (2016). Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by topo-isomerase I inhibitors. eLife, 5(JUN2016), [e14709]. https://doi.org/10.7554/eLife.14709