Yamamoto Kenta, Wang Jiguang, Sprinzen Lisa, Xu Jun, Haddock Christopher J, Li Chen, Lee Brian J, Loredan Denis G, Jiang Wenxia, Vindigni Alessandro, Wang Dong, Rabadan Raul, Zha Shan
Institute for Cancer Genetics, Columbia Unviersity, New York, United States.
Department of Pathology and Cell Biology, Columbia University, New York, United States.
Elife. 2016 Jun 15;5:e14709. doi: 10.7554/eLife.14709.
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.
ATM激酶是DNA损伤反应的主要调节因子，其错义突变在许多癌症中都有发现，但它们对ATM功能的影响以及对癌症治疗的意义在很大程度上尚不清楚。在此，我们报告称，72%的与癌症相关的ATM突变是错义突变，且在激酶结构域周围富集。在小鼠模型中，激酶失活的ATM（Atm(KD/-)）比ATM缺失（Atm(-/-)）更具致癌性，会导致更早且更频繁地发生伴有Pten缺失的淋巴瘤。激酶失活的ATM蛋白（Atm-KD）而非ATM缺失（Atm-null）会在链断裂步骤阻止依赖复制的拓扑异构酶I-DNA加合物的去除，导致严重的基因组不稳定以及对拓扑异构酶I抑制剂的超敏反应。相应地，在动物模型中，拓扑异构酶I抑制剂能有效且优先消除Atm(KD/-)白血病，但对ATM功能正常或Atm(-/-)的白血病无效。这些发现确定了ATM激酶结构域错义突变是一种强大的致癌事件以及基于拓扑异构酶I抑制剂治疗的生物标志物。
