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.

Notch is a direct negative regulator of the DNA-damage response / J. Vermezovic, M. Adamowicz, L. Santarpia, A. Rustighi, M. Forcato, C. Lucano, L. Massimiliano, V. Costanzo, S. Bicciato, G. Del Sal, F. d'Adda di Fagagna. - In: NATURE STRUCTURAL & MOLECULAR BIOLOGY. - ISSN 1545-9985. - 22:5(2015 May), pp. 417-424. [10.1038/nsmb.3013]

Notch is a direct negative regulator of the DNA-damage response

J. Vermezovic;M. Adamowicz;V. Costanzo
Conceptualization
;
2015

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.
Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Binding Sites; Caenorhabditis elegans; Cell Line, Tumor; DNA Damage; DNA Repair; DNA-Binding Proteins; Enzyme Activation; HEK293 Cells; HeLa Cells; Humans; Multiprotein Complexes; Neoplasms; Protein Binding; Protein Structure, Tertiary; Receptor, Notch1; Signal Transduction; Transcription, Genetic; Xenopus laevis
Settore MED/04 - Patologia Generale
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/577860
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