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

Jelena Vermezovic, Marek Adamowicz, Libero Santarpia, Alessandra Rustighi, Mattia Forcato, Caterina Lucano, Lucia Massimiliano, Vincenzo Costanzo, Silvio Bicciato, Giannino Del Sal, Fabrizio D'Adda Di Fagagna

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)417-424
Number of pages8
JournalNature Structural and Molecular Biology
Volume22
Issue number5
DOIs
Publication statusPublished - May 11 2015

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology
  • Medicine(all)

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    Vermezovic, J., Adamowicz, M., Santarpia, L., Rustighi, A., Forcato, M., Lucano, C., Massimiliano, L., Costanzo, V., Bicciato, S., Del Sal, G., & D'Adda Di Fagagna, F. (2015). Notch is a direct negative regulator of the DNA-damage response. Nature Structural and Molecular Biology, 22(5), 417-424. https://doi.org/10.1038/nsmb.3013