title: NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5/Tip60 Complex.
abstract: The DNA damage response (DDR) signal transduction pathway is responsible for sensing DNA damage and further relaying this signal into the cell. ATM is an apical DDR kinase that orchestrates the activation and the recruitment of downstream DDR factors to induce cell-cycle arrest and repair. We have previously shown that NOTCH1 inhibits ATM activation upon DNA damage, but the underlying mechanism remains unclear. Here, we show that NOTCH1 does not impair ATM recruitment to DNA double-strand breaks (DSBs). Rather, NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM through a mechanism in which NOTCH1 competes with FOXO3a for ATM binding. Lack of FOXO3a binding to ATM leads to the loss of KAT5/Tip60 association with ATM. Moreover, expression of NOTCH1 or depletion of ATM impairs the formation of the FOXO3a-KAT5/Tip60 protein complex. Finally, we show that pharmacological induction of FOXO3a nuclear localization sensitizes NOTCH1-driven cancers to DNA-damage-induced cell death.
authors.affiliation: IFOM Foundation, FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy.
authors.forename: Marek
authors.initials: M
authors.lastname: Adamowicz
authors.affiliation: IFOM Foundation, FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy.
authors.forename: Jelena
authors.initials: J
authors.lastname: Vermezovic
authors.affiliation: IFOM Foundation, FIRC Institute of Molecular Oncology Foundation, 20139 Milan, Italy; Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, 27100 Pavia, Italy. Electronic address: fabrizio.dadda@ifom.eu.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D001667:Binding, Competitive; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D000071316:Forkhead Box Protein O3 / Q000235:genetics* / Q000378:metabolism; D005720:Gamma Rays; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D000074443:Lysine Acetyltransferase 5 / Q000235:genetics* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011485:Protein Binding; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D008687:Metformin; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins