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The eEF2 kinase coordinates the DNA damage response to cisplatin by supporting p53 activation.

Published version
Peer-reviewed

Repository DOI


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Authors

Samiei, Arash 
Delaidelli, Alberto 
de Santis, Jessica Oliveira 

Abstract

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a stress-responsive hub that inhibits the translation elongation factor eEF2, and consequently mRNA translation elongation, in response to hypoxia and nutrient deprivation. EEF2K is also involved in the response to DNA damage but its role in response to DNA crosslinks, as induced by cisplatin, is not known. Here we found that eEF2K is critical to mediate the cellular response to cisplatin. We uncovered that eEF2K deficient cells are more resistant to cisplatin treatment. Mechanistically, eEF2K deficiency blunts the activation of the DNA damage response associated ATM and ATR pathways, in turn preventing p53 activation and therefore compromising induction of cisplatin-induced apoptosis. We also report that loss of eEF2K delays the resolution of DNA damage triggered by cisplatin, suggesting that eEF2K contributes to DNA damage repair in response to cisplatin. In support of this, our data shows that eEF2K promotes the expression of the DNA repair protein ERCC1, critical for the repair of cisplatin-caused DNA damage. Finally, using Caenorhabditis elegans as an in vivo model, we find that deletion of efk-1, the worm eEF2K ortholog, mitigates the induction of germ cell death in response to cisplatin. Together, our data highlight that eEF2K represents an evolutionary conserved mediator of the DNA damage response to cisplatin which promotes p53 activation to induce cell death, or alternatively facilitates DNA repair, depending on the extent of DNA damage.

Description

Acknowledgements: We would like to thank Vlada Bezdezhskaya and Julia Harz for their technical help. This work was supported in part by funds from CIHR Foundation grant FDN-143280 (to P.H.S.). G.L. was supported by a grant from the German Cancer Aid (grant no. 70112624). J.K.M.L was supported by the Deutsche Forschungsgemeinschaft (Walter Benjamin Fellowship no. LI3844/1-1) and the Research Commission of the Medical Faculty, Heinrich Heine University Düsseldorf (grant no. 2022-12). C.J.C. was funded by CRUK Discovery Award DRCPGM\100005.

Keywords

Cisplatin, Tumor Suppressor Protein p53, Elongation Factor 2 Kinase, DNA Damage, Animals, Caenorhabditis elegans, Humans, DNA Repair, Ataxia Telangiectasia Mutated Proteins, Apoptosis

Journal Title

Cell Death Dis

Conference Name

Journal ISSN

2041-4889
2041-4889

Volume Title

15

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (DRCPGM\100005)