title: Notch is a direct negative regulator of the DNA-damage response.
abstract: The DNA-damage response (DDR) ensures genome stability and proper inheritance of genetic information, both of which are essential to survival. It is presently unclear to what extent other signaling pathways modulate DDR function. Here we show that Notch receptor binds and inactivates ATM kinase and that this mechanism is evolutionarily conserved in Caenorhabditis elegans, Xenopus laevis and humans. In C. elegans, the Notch pathway impairs DDR signaling in gonad germ cells. In mammalian cells, activation of human Notch1 leads to reduced ATM signaling in a manner independent of Notch1 transcriptional activity. Notch1 binds directly to the regulatory FATC domain of ATM and inhibits ATM kinase activity. Notch1 and ATM activation are inversely correlated in human breast cancers, and inactivation of ATM by Notch1 contributes to the survival of Notch1-driven leukemia cells upon DNA damage.
authors.affiliation: Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, Milan, Italy.
authors.forename: Jelena
authors.initials: J
authors.lastname: Vermezovic
authors.affiliation: Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, Milan, Italy.
authors.forename: Marek
authors.initials: M
authors.lastname: Adamowicz
authors.affiliation: Experimental Therapeutics Unit, Istituto di Ricovero e Cura a Carattere Scientifico Humanitas Clinical and Research Institute, Milan, Italy.
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
authors.affiliation: 1] Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Trieste, Italy. [2] Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rustighi
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Mattia
authors.identifier: 0000000273836576
authors.initials: M
authors.lastname: Forcato
authors.affiliation: Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Lucano
authors.affiliation: European Institute of Oncology, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Massimiliano
authors.affiliation: Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
authors.affiliation: Center for Genome Research, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvio
authors.identifier: 0000000219447078
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: 1] Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Trieste, Italy. [2] Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Giannino
authors.initials: G
authors.lastname: Del Sal
authors.affiliation: 1] Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, Milan, Italy. [2] Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: d'Adda di Fagagna
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D014982:Xenopus laevis / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins