Abstract
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.
| Original language | American English |
|---|---|
| Article number | 5760 |
| Pages (from-to) | 5760 |
| Journal | Scientific Reports |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
Bibliographical note
Funding Information:We thank Dr. G. Zamir from the Department of Surgery, Hadassah Hebrew-University Medical Center, Jerusalem, Israel, for providing the primary normal human dermal fibroblasts (HF). Sequencing, quality control, and differential expression analyses were conducted by the "Technion Genome Center". We would also like to thank Sharona Elgavish and Hadar Benyamini from the I-CORE Bioinformatics Unit of the Hebrew University of Jerusalem and Hadassah Medical Center for Bioinformatics data analysis. We would like to thank Dr. F. Rosl for critical discussions and reading of the manuscript. Special thanks to the late Dr. Ulrich Rodeck for his friendship and critical discussions. This work was supported in part by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science, Technology and Space (MOST). Y. V. was supported by ERC advance?GA No. 786575?RxmiRcanceR. E.G. was supported by grants from the NIH CA197081-02, the MOST, the ISF collaboration with Canada (2473/2017), the personal ISF (486/2017 and the ISF and ICORE?(ISF 41/2011), the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841) and the ERC advance?GA No. 786575?RxmiRcanceR (EG). The work of EG was also supported by the Kron, Raskin and the Robert Benson foundations.
Funding Information:
We thank Dr. G. Zamir from the Department of Surgery, Hadassah Hebrew-University Medical Center, Jerusalem, Israel, for providing the primary normal human dermal fibroblasts (HF). Sequencing, quality control, and differential expression analyses were conducted by the "Technion Genome Center". We would also like to thank Sharona Elgavish and Hadar Benyamini from the I-CORE Bioinformatics Unit of the Hebrew University of Jerusalem and Hadassah Medical Center for Bioinformatics data analysis. We would like to thank Dr. F. Rosl for critical discussions and reading of the manuscript. Special thanks to the late Dr. Ulrich Rodeck for his friendship and critical discussions. This work was supported in part by the Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ) and Israel's Ministry of Science, Technology and Space (MOST). Y. V. was supported by ERC advance—GA No. 786575—RxmiRcanceR. E.G. was supported by grants from the NIH CA197081-02, the MOST, the ISF collaboration with Canada (2473/2017), the personal ISF (486/2017 and the ISF and ICORE—(ISF 41/2011), the Deutsche Forschungsgemeinschaft, Bonn, Germany (SFB841) and the ERC advance—GA No. 786575—RxmiRcanceR (EG). The work of EG was also supported by the Kron, Raskin and the Robert Benson foundations.
Publisher Copyright:
© 2022, The Author(s).
Keywords
- DNA
- DNA Breaks, Double-Stranded
- DNA Damage
- DNA Repair
- ErbB Receptors/genetics