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.
Highlights
ATM kinase is a tumor suppressor that has a central role in the DNA damage responses
~ of ATM missense mutations in The Cancer Genome Atlas (TCGA) that are concurrent with heterozygous loss of ATM or truncating mutations in the same case, and found that, again, ATM missense mutations cluster around the C-terminal kinase domain even in this smaller subset (Figure 1B)
While previous studies have mostly focused on the complete loss of ATM (Atm-/, truncating mutations), recent sequencing analyses identified a large number of missense ATM mutations in human cancers with limited information on their biological function
Summary
ATM kinase is a tumor suppressor that has a central role in the DNA damage responses. Germline inactivation of ATM causes ataxia-telangiectasia (A-T), which is associated with greatly increased risk of lymphoma and leukemia (Lavin, 2008). Somatic mutations of ATM occur frequently in mantle cell lymphomas (MCL), chronic lymphoblastic leukemia (CLL) and T-cell prolymphocytic leukemia. Cell Biology eLife digest Cancer is a genetic disease. It is essential that cells do not accrue too many dangerous mutations in their DNA that allow cancers to grow and develop. DNA damage activates ATM, which, in turn, adds phosphate groups to other proteins. These newly tagged proteins stop cells dividing until the DNA has been repaired
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