TY  - JOUR
AU  - Volman, Yael
AU  - Hefetz, Ruth
AU  - Galun, Eithan
AU  - Rachmilewitz, Jacob
TI  - DNA damage alters EGFR signaling and reprograms cellular response via Mre-11.
JO  - Scientific reports
VL  - 12
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-02412
SP  - 5760
PY  - 2022
N1  - #DKFZ-MOST-Ca182#
AB  - To combat the various DNA lesions and their harmful effects, cells have evolved different strategies, collectively referred as DNA damage response (DDR). The DDR largely relies on intranuclear protein networks, which sense DNA lesions, recruit DNA repair enzymes, and coordinates several aspects of the cellular response, including a temporary cell cycle arrest. In addition, external cues mediated by the surface EGF receptor (EGFR) through downstream signaling pathways contribute to the cellular DNA repair capacity. However, cell cycle progression driven by EGFR activation should be reconciled with cell cycle arrest necessary for effective DNA repair. Here, we show that in damaged cells, the expression of Mig-6 (mitogen-inducible gene 6), a known regulator of EGFR signaling, is reduced resulting in heightened EGFR phosphorylation and downstream signaling. These changes in Mig-6 expression and EGFR signaling do not occur in cells deficient of Mre-11, a component of the MRN complex, playing a central role in double-strand break (DSB) repair or when cells are treated with the MRN inhibitor, mirin. RNAseq and functional analysis reveal that DNA damage induces a shift in cell response to EGFR triggering that potentiates DDR-induced p53 pathway and cell cycle arrest. These data demonstrate that the cellular response to EGFR triggering is skewed by components of the DDR, thus providing a plausible explanation for the paradox of the known role played by a growth factor such as EGFR in the DNA damage repair.
KW  - DNA
KW  - DNA Breaks, Double-Stranded
KW  - DNA Damage
KW  - DNA Repair
KW  - ErbB Receptors: genetics
KW  - DNA (NLM Chemicals)
KW  - ErbB Receptors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:35388101
C2  - pmc:PMC8986772
DO  - DOI:10.1038/s41598-022-09779-5
UR  - https://inrepo02.dkfz.de/record/305795
ER  -