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.

journal_name

Nat Struct Mol Biol

authors

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

doi

10.1038/nsmb.3013

subject

Has Abstract

pub_date

2015-05-01 00:00:00

pages

417-24

issue

5

eissn

1545-9993

issn

1545-9985

pii

nsmb.3013

journal_volume

22

pub_type

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