{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:35:35Z","timestamp":1791293735569,"version":"4.1.0"},"reference-count":113,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T00:00:00Z","timestamp":1641254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ataxia\u2013telangiectasia mutated (ATM) functions as a key initiator and coordinator of DNA damage and cellular stress responses. ATM signaling pathways contain many downstream targets that regulate multiple important cellular processes, including DNA damage repair, apoptosis, cell cycle arrest, oxidative sensing, and proliferation. Over the past few decades, associations between germline ATM pathogenic variants and cancer risk have been reported, particularly for breast and pancreatic cancers. In addition, given that ATM plays a critical role in repairing double-strand breaks, inhibiting other DNA repair pathways could be a synthetic lethal approach. Based on this rationale, several DNA damage response inhibitors are currently being tested in ATM-deficient cancers. In this review, we discuss the current knowledge related to the structure of the ATM gene, function of ATM kinase, clinical significance of ATM germline pathogenic variants in patients with hereditary cancers, and ongoing efforts to target ATM for the benefit of cancer patients.<\/jats:p>","DOI":"10.3390\/ijms23010523","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T01:15:26Z","timestamp":1641518126000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["ATM: Functions of ATM Kinase and Its Relevance to Hereditary Tumors"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1138-5631","authenticated-orcid":false,"given":"Sayaka","family":"Ueno","sequence":"first","affiliation":[{"name":"Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji-cho, Akashi-shi 673-8558, Japan"},{"name":"Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamotsu","family":"Sudo","sequence":"additional","affiliation":[{"name":"Section of Translational Research, Hyogo Cancer Center, 13-70 Kita-Oji-cho, Akashi-shi 673-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4124-5488","authenticated-orcid":false,"given":"Akira","family":"Hirasawa","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomic Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,4]]},"reference":[{"key":"ref_1","first-page":"15","article-title":"Ataxia-telangiectasia. A familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. A preliminary report on 7 children, an autopsy, and a case history","volume":"9","author":"Boder","year":"1957","journal-title":"Univ. S. Calif. Med. Bull."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1186\/s13023-016-0543-7","article-title":"Ataxia telangiectasia: A review","volume":"11","author":"Wright","year":"2016","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/cge.12453","article-title":"Ataxia telangiectasia: More variation at clinical and cellular levels","volume":"87","author":"Taylor","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1126\/science.7792600","article-title":"A single ataxia telangiectasia gene with a product similar to PI-3 kinase","volume":"268","author":"Savitsky","year":"1995","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1038\/bjc.2011.266","article-title":"Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours","volume":"105","author":"Reiman","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1200\/JCO.2014.56.5101","article-title":"Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: A report from the French national registry of primary immune deficiencies","volume":"33","author":"Suarez","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"574","DOI":"10.3109\/08880018.2013.777949","article-title":"Acute lymphoblastic leukemia in early childhood as the presenting sign of ataxia-telangiectasia variant","volume":"30","author":"Bielorai","year":"2013","journal-title":"Pediatr. Hematol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1017\/S0317167100007794","article-title":"Ataxia-telangiectasia: Atypical presentation and toxicity of cancer treatment","volume":"36","author":"Yanofsky","year":"2009","journal-title":"Can. J. Neurol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1056\/NEJM198705213162101","article-title":"Breast and other cancers in families with ataxia-telangiectasia","volume":"316","author":"Swift","year":"1987","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cell.2018.03.039","article-title":"Pathogenic Germline Variants in 10,389 Adult Cancers","volume":"173","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1158\/1940-6207.CAPR-20-0448","article-title":"Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers","volume":"14","author":"Hall","year":"2021","journal-title":"Cancer Prev. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/cge.12710","article-title":"Health risks for ataxia-telangiectasia mutated heterozygotes: A systematic review, meta-analysis and evidence-based guideline","volume":"90","author":"Roeleveld","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1146\/annurev-biochem-060614-034335","article-title":"Mechanisms of ATM Activation","volume":"84","author":"Paull","year":"2015","journal-title":"Annu. Rev. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e104400","DOI":"10.15252\/embj.2020104400","article-title":"Phosphoproteomics reveals novel modes of function and inter-relationships among PIKKs in response to genotoxic stress","volume":"40","author":"Bensimon","year":"2021","journal-title":"EMBO J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1126\/science.1192912","article-title":"ATM activation by oxidative stress","volume":"330","author":"Guo","year":"2010","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e1700933","DOI":"10.1126\/sciadv.1700933","article-title":"Structures of closed and open conformations of dimeric human ATM","volume":"3","author":"Pollard","year":"2017","journal-title":"Sci. Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.str.2019.10.012","article-title":"Cryo-EM Structure of Nucleotide-Bound Tel1(ATM) Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations","volume":"28","author":"Yates","year":"2020","journal-title":"Structure"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1073\/pnas.1416031112","article-title":"ATM prevents DSB formation by coordinating SSB repair and cell cycle progression","volume":"112","author":"Khoronenkova","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1083\/jcb.201806197","article-title":"ATM is activated by ATP depletion and modulates mitochondrial function through NRF1","volume":"218","author":"Chow","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_21","first-page":"1669","article-title":"Mechanisms of Non-canonical Activation of Ataxia Telangiectasia Mutated","volume":"81","author":"Khoronenkova","year":"2016","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101972","DOI":"10.1016\/j.isci.2020.101972","article-title":"Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia","volume":"24","author":"Yeo","year":"2021","journal-title":"iScience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1038\/s41422-019-0205-0","article-title":"Structural insights into the activation of ATM kinase","volume":"29","author":"Xiao","year":"2019","journal-title":"Cell Res"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1101\/sqb.2000.65.127","article-title":"Repair of Endogenous DNA Damage","volume":"65","author":"Lindahl","year":"2000","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1056\/NEJMra0804615","article-title":"DNA damage, aging, and cancer","volume":"361","author":"Hoeijmakers","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrm1907","article-title":"The multifaceted mismatch-repair system","volume":"7","author":"Jiricny","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/nrg2380","article-title":"Single-strand break repair and genetic disease","volume":"9","author":"Caldecott","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA damage response: Making it safe to play with knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41586-018-0497-0","article-title":"Population dynamics of normal human blood inferred from somatic mutations","volume":"561","author":"Shepherd","year":"2018","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1126\/science.aan8690","article-title":"Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis","volume":"359","author":"Bae","year":"2018","journal-title":"Science"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1038\/s41467-020-14844-6","article-title":"Measuring single cell divisions in human tissues from multi-region sequencing data","volume":"11","author":"Werner","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1093\/nar\/gkn550","article-title":"Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin","volume":"36","author":"Kinner","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1002\/embj.201386064","article-title":"Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks","volume":"33","author":"Wang","year":"2014","journal-title":"EMBO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/nature03442","article-title":"Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage","volume":"434","author":"Falck","year":"2005","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Mand, M.R., Kao, C.H., Zhou, Y., Ryu, S.W., Richards, A.L., Coon, J.J., and Paull, T.T. (2018). ATM directs DNA damage responses and proteostasis via genetically separable pathways. Sci. Signal., 11.","DOI":"10.1126\/scisignal.aan5598"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nature01368","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation","volume":"421","author":"Bakkenist","year":"2003","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1083\/jcb.200906064","article-title":"Autophosphorylation at serine 1981 stabilizes ATM at DNA damage sites","volume":"187","author":"So","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9107","DOI":"10.1074\/jbc.M110.204065","article-title":"Autophosphorylation and ATM activation: Additional sites add to the complexity","volume":"286","author":"Kozlov","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13182","DOI":"10.1073\/pnas.0504211102","article-title":"A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM","volume":"102","author":"Sun","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.3390\/biom5042877","article-title":"ATM-Dependent Phosphorylation of All Three Members of the MRN Complex: From Sensor to Adaptor","volume":"5","author":"Lavin","year":"2015","journal-title":"Biomolecules"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1038\/s41467-019-09641-9","article-title":"Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks","volume":"10","author":"Ha","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102948","DOI":"10.1016\/j.dnarep.2020.102948","article-title":"Roles for MDC1 in cancer development and treatment","volume":"95","author":"Ruff","year":"2020","journal-title":"DNA Repair"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.molcel.2012.05.052","article-title":"Quantitative live cell imaging reveals a gradual shift between DNA repair mechanisms and a maximal use of HR in mid S phase","volume":"47","author":"Karanam","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Wang, H., Shi, L.Z., Wong, C.C., Han, X., Hwang, P.Y., Truong, L.N., Zhu, Q., Shao, Z., Chen, D.J., and Berns, M.W. (2013). The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR-mediated double-strand break repair. PLoS Genet., 9.","DOI":"10.1371\/journal.pgen.1003277"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"eabd9208","DOI":"10.1126\/sciadv.abd9208","article-title":"ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication","volume":"7","author":"Wang","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1101\/gad.333237.119","article-title":"53BP1: A DSB escort","volume":"34","author":"Mirman","year":"2020","journal-title":"Genes. Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6582","DOI":"10.1074\/jbc.M611605200","article-title":"Ataxia telangiectasia mutated (ATM) is essential for DNA-PKcs phosphorylations at the Thr-2609 cluster upon DNA double strand break","volume":"282","author":"Chen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nrm.2017.48","article-title":"Non-homologous DNA end joining and alternative pathways to double-strand break repair","volume":"18","author":"Chang","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"19389","DOI":"10.1074\/jbc.M200822200","article-title":"Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain","volume":"277","author":"Ahn","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1128\/MCB.22.12.4419-4432.2002","article-title":"Chk2 activation and phosphorylation-dependent oligomerization","volume":"22","author":"Xu","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"60807","DOI":"10.18632\/oncotarget.11845","article-title":"Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer","volume":"7","author":"Weber","year":"2016","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"472","DOI":"10.4161\/cc.9.3.10556","article-title":"Mechanism of p53 stabilization by ATM after DNA damage","volume":"9","author":"Cheng","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1126\/science.287.5459.1824","article-title":"DNA damage-induced activation of p53 by the checkpoint kinase Chk2","volume":"287","author":"Hirao","year":"2000","journal-title":"Science"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nrc2657","article-title":"p21 in cancer: Intricate networks and multiple activities","volume":"9","author":"Abbas","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrc3711","article-title":"Unravelling mechanisms of p53-mediated tumour suppression","volume":"14","author":"Bieging","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1038\/sj.emboj.7601733","article-title":"ATMIN defines an NBS1-independent pathway of ATM signalling","volume":"26","author":"Kanu","year":"2007","journal-title":"EMBO J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.celrep.2012.11.002","article-title":"Competition between NBS1 and ATMIN controls ATM signaling pathway choice","volume":"2","author":"Zhang","year":"2012","journal-title":"Cell. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"38222","DOI":"10.1074\/jbc.M204409200","article-title":"ATM is activated in response to N-methyl-N\u2019-nitro-N-nitrosoguanidine-induced DNA alkylation","volume":"277","author":"Adamson","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Lee, J.H., Paull, T.T., Gehrke, S., D\u2019Alessandro, A., Dou, Q., Gladyshev, V.N., Schroeder, E.A., Steyl, S.K., and Christian, B.E. (2018). Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity. Sci. Signal., 11.","DOI":"10.1126\/scisignal.aaq0702"},{"key":"ref_60","first-page":"1849","article-title":"Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice","volume":"61","author":"Kamsler","year":"2001","journal-title":"Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Ehrenfeld, V., Heusel, J.R., Fulda, S., and van Wijk, S.J.L. (2020). ATM inhibition enhances Auranofin-induced oxidative stress and cell death in lung cell lines. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0244060"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"14396","DOI":"10.1074\/jbc.M808116200","article-title":"Oxidative stress is linked to ERK1\/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes","volume":"284","author":"Kim","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1182\/blood-2011-08-373639","article-title":"Mitochondrial dysfunction in ataxia-telangiectasia","volume":"119","author":"Maclean","year":"2012","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"101511","DOI":"10.1016\/j.redox.2020.101511","article-title":"Mitochondria at the crossroads of ATM-mediated stress signaling and regulation of reactive oxygen species","volume":"32","author":"Lee","year":"2020","journal-title":"Redox. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2723","DOI":"10.1172\/JCI31604","article-title":"Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis","volume":"117","author":"Eaton","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1093\/hmg\/ddm166","article-title":"Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells","volume":"16","author":"Ambrose","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.cmet.2016.09.004","article-title":"NAD(+) Replenishment Improves Lifespan and Healthspan in Ataxia Telangiectasia Models via Mitophagy and DNA Repair","volume":"24","author":"Fang","year":"2016","journal-title":"Cell Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e50500","DOI":"10.15252\/embr.202050500","article-title":"Redox activation of ATM enhances GSNOR translation to sustain mitophagy and tolerance to oxidative stress","volume":"22","author":"Cirotti","year":"2021","journal-title":"EMBO Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1073\/pnas.0913860107","article-title":"ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS","volume":"107","author":"Alexander","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1038\/s41401-018-0047-1","article-title":"Aescin-induced reactive oxygen species play a pro-survival role in human cancer cells via ATM\/AMPK\/ULK1-mediated autophagy","volume":"39","author":"Li","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e103111","DOI":"10.15252\/embj.2019103111","article-title":"ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress","volume":"39","author":"Guo","year":"2020","journal-title":"EMBO J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1016\/j.bbamcr.2006.09.006","article-title":"Peroxisomes and oxidative stress","volume":"1763","author":"Schrader","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1038\/ncb3230","article-title":"ATM functions at the peroxisome to induce pexophagy in response to ROS","volume":"17","author":"Zhang","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1080\/15548627.2015.1123375","article-title":"A new role for ATM in selective autophagy of peroxisomes (pexophagy)","volume":"12","author":"Tripathi","year":"2016","journal-title":"Autophagy"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.cell.2017.01.002","article-title":"Endogenous DNA Damage as a Source of Genomic Instability in Cancer","volume":"168","author":"Tubbs","year":"2017","journal-title":"Cell"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5148","DOI":"10.1158\/0008-5472.CAN-04-0442","article-title":"Effect of N-acetyl cysteine on oxidative DNA damage and the frequency of DNA deletions in atm-deficient mice","volume":"64","author":"Reliene","year":"2004","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1073\/pnas.1418139112","article-title":"NADPH oxidase 4 is a critical mediator in Ataxia telangiectasia disease","volume":"112","author":"Weyemi","year":"2015","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.jmoldx.2019.03.001","article-title":"Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines","volume":"21","author":"Neben","year":"2019","journal-title":"J. Mol. Diagn."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.cancergen.2017.01.002","article-title":"Detection of somatic variants in peripheral blood lymphocytes using a next generation sequencing multigene pan cancer panel","volume":"211","author":"Coffee","year":"2017","journal-title":"Cancer Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/gim.2017.196","article-title":"Somatic TP53 variants frequently confound germ-line testing results","volume":"20","author":"Weitzel","year":"2018","journal-title":"Genet. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.1182\/blood-2018-03-840629","article-title":"Detection of clonal hematopoiesis of indeterminate potential in clinical sequencing of solid tumor specimens","volume":"131","author":"Severson","year":"2018","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2477","DOI":"10.1056\/NEJMoa1409405","article-title":"Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence","volume":"371","author":"Genovese","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/s41436-021-01138-5","article-title":"Incidental detection of acquired variants in germline genetic and genomic testing: A points to consider statement of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Chao","year":"2021","journal-title":"Genet. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/jnci\/djaa023","article-title":"The Contribution of Germline Predisposition Gene Mutations to Clinical Subtypes of Invasive Breast Cancer From a Clinical Genetic Testing Cohort","volume":"112","author":"Hu","year":"2020","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1001\/jamaoncol.2017.0424","article-title":"Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer","volume":"3","author":"Couch","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1056\/NEJMsr1501341","article-title":"Gene-panel sequencing and the prediction of breast-cancer risk","volume":"372","author":"Easton","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1136\/jmedgenet-2016-103839","article-title":"PALB2, CHEK2 and ATM rare variants and cancer risk: Data from COGS","volume":"53","author":"Southey","year":"2016","journal-title":"J. Med. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"R73","DOI":"10.1186\/bcr2919","article-title":"Rare variants in the ATM gene and risk of breast cancer","volume":"13","author":"Goldgar","year":"2011","journal-title":"Breast Cancer Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/gim.2017.85","article-title":"Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history","volume":"20","author":"Chaffee","year":"2018","journal-title":"Genet. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1001\/jama.2018.6228","article-title":"Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer","volume":"319","author":"Hu","year":"2018","journal-title":"JAMA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1200\/JCO.2017.72.3502","article-title":"Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma","volume":"35","author":"Shindo","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1200\/JCO.18.01512","article-title":"Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance","volume":"37","author":"Abe","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1053\/j.gastro.2018.05.035","article-title":"Risk of Neoplastic Progression in Individuals at High Risk for Pancreatic Cancer Undergoing Long-term Surveillance","volume":"155","author":"Canto","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1200\/JCO.2015.64.0730","article-title":"Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers","volume":"34","author":"Vasen","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.eururo.2016.11.033","article-title":"Germline Mutations in ATM and BRCA1\/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death","volume":"71","author":"Na","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.euo.2020.12.001","article-title":"Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study","volume":"4","author":"Karlsson","year":"2021","journal-title":"Eur. Urol. Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1200\/JCO.18.01854","article-title":"Genetic Testing and Results in a Population-Based Cohort of Breast Cancer Patients and Ovarian Cancer Patients","volume":"37","author":"Kurian","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.ygyno.2017.08.030","article-title":"Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls","volume":"147","author":"Lilyquist","year":"2017","journal-title":"Gynecol. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.ygyno.2019.01.027","article-title":"Large-scale meta-analysis of mutations identified in panels of breast\/ovarian cancer-related genes\u2014Providing evidence of cancer predisposition genes","volume":"153","author":"Suszynska","year":"2019","journal-title":"Gynecol. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/s41436-021-01240-8","article-title":"Germline ATM variants predispose to melanoma: A joint analysis across the GenoMEL and MelaNostrum consortia","volume":"23","author":"Dalmasso","year":"2021","journal-title":"Genet. Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1038\/s41436-021-01172-3","article-title":"ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"Miller","year":"2021","journal-title":"Genet. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1093\/annonc\/mdz136","article-title":"Germline-focussed analysis of tumour-only sequencing: Recommendations from the ESMO Precision Medicine Working Group","volume":"30","author":"Mandelker","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1056\/NEJMoa1603144","article-title":"Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer","volume":"375","author":"Pritchard","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.cell.2015.05.001","article-title":"Integrative clinical genomics of advanced prostate cancer","volume":"161","author":"Robinson","year":"2015","journal-title":"Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"11428","DOI":"10.1073\/pnas.1902651116","article-title":"Genomic correlates of clinical outcome in advanced prostate cancer","volume":"116","author":"Abida","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1470-2045(19)30684-9","article-title":"Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): A multicentre, open-label, randomised, phase 2 trial","volume":"21","author":"Mateo","year":"2020","journal-title":"Lancet. Oncol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1056\/NEJMoa1911440","article-title":"Olaparib for Metastatic Castration-Resistant Prostate Cancer","volume":"382","author":"Mateo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1056\/NEJMoa2022485","article-title":"Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer","volume":"383","author":"Hussain","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1158\/0008-5472.CAN-19-3126","article-title":"ATM Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer","volume":"80","author":"Rafiei","year":"2020","journal-title":"Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nchembio.573","article-title":"Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR","volume":"7","author":"Reaper","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4869","DOI":"10.1038\/s41388-020-1328-y","article-title":"Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells","volume":"39","author":"Lloyd","year":"2020","journal-title":"Oncogene"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1158\/2159-8290.CD-20-0868","article-title":"First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors","volume":"11","author":"Yap","year":"2021","journal-title":"Cancer Discov."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:36:05Z","timestamp":1760362565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/1\/523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,4]]},"references-count":113,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23010523"],"URL":"https:\/\/doi.org\/10.3390\/ijms23010523","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,4]]}}}