Notch is a Direct Negative Regulator of the DNA-damage Response

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2015 Apr 21

PMID 25895060

Citations 43

Authors

Jelena Vermezovic

Marek Adamowicz

Libero Santarpia

Alessandra Rustighi

Mattia Forcato

Caterina Lucano

Lucia Massimiliano

Vincenzo Costanzo

Silvio Bicciato

Giannino Del Sal

Fabrizio dAdda di Fagagna

Affiliations

Soon will be listed here.

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.

Citing Articles

NOTCH1 regulates the DNA damage response and sorafenib resistance by activating ATM in hepatocellular carcinoma.

Liu J, Yu Y, Xu B, Liang Q, Fang T, Zhou N Am J Transl Res. 2025; 16(12):7317-7329.

PMID: 39822534 PMC: 11733373. DOI: 10.62347/EAFU3015.

BCAT1 Associates with DNA Repair Proteins KU70 and KU80 and Contributes to Regulate DNA Repair in T-Cell Acute Lymphoblastic Leukemia (T-ALL).

Tosello V, Rompietti C, Papathanassiu A, Arrigoni G, Piovan E Int J Mol Sci. 2025; 25(24.

PMID: 39769333 PMC: 11676169. DOI: 10.3390/ijms252413571.

Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control.

Huang X, Chen W, Wang Y, Shytikov D, Wang Y, Zhu W Front Med. 2025; 19(1):23-52.

PMID: 39745621 DOI: 10.1007/s11684-024-1107-1.

Branching NOTCH1 to DNA damage in T-cell acute lymphoblastic leukemia.

Kulkarni T, Herranz D Haematologica. 2024; 110(2):270-272.

PMID: 39445418 PMC: 11788615. DOI: 10.3324/haematol.2024.286450.

BCAT1 is a NOTCH1 target and sustains the oncogenic function of NOTCH1.

Tosello V, Di Martino L, Papathanassiu A, Santa S, Pizzi M, Mussolin L Haematologica. 2024; 110(2):350-367.

PMID: 39234857 PMC: 11788623. DOI: 10.3324/haematol.2024.285552.

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