{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yamamoto K"],"funding":["American Cancer Society","NCATS NIH HHS","National Cancer Institute","NCI NIH HHS","National Institute of General Medical Sciences","NIGMS NIH HHS","Leukemia and Lymphoma Society"],"pagination":["e14709"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4957979"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5"],"pubmed_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 e"],"journal":["eLife"],"pubmed_title":["Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors."],"pmcid":["PMC4957979"],"funding_grant_id":["R01 GM108648","T32 CA009503","UL1 TR000040","1R01CA185486-01","R01 CA158073","NIH/NIGMS GM102362","5R01CA184187","1R01CA179044-01A1","Scholar Award","R01 CA179044","NIH R01GM108648","P01 CA174653","1P01CA174653","RSG-13-038-01 DMC","R01 CA185486","R01 CA184187","T32-CA09503","R01 GM102362","U54 CA193313","1R01CA158073"],"pubmed_authors":["Rabadan R","Yamamoto K","Haddock CJ","Zha S","Li C","Sprinzen L","Wang D","Loredan DG","Wang J","Xu J","Lee BJ","Jiang W","Vindigni A"],"additional_accession":[]},"is_claimable":false,"name":"Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors.","description":"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 e","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Jun","modification":"2026-04-07T17:01:50.785Z","creation":"2019-03-27T02:19:00Z"},"accession":"S-EPMC4957979","cross_references":{"pubmed":["27304073"],"doi":["10.7554/eLife.14709"]}}