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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

AsiDNA is a DNA repair inhibitor mimicking DNA double-strand breaks (DSB) that was designed to disorganize DSB repair pathways to sensitize tumors to DNA damaging therapies such as radiotherapy and chemotherapy. We used the property of AsiDNA of triggering artificial DNA damage signaling to examine the activation of DSB repair pathways and to study the main steps of inhibition of DNA repair foci after irradiation. We show that, upon AsiDNA cellular uptake, cytoplasmic ATM and PARP are rapidly activated (within one hour) even in the absence of irradiation. ATM activation by AsiDNA leads to its transient autophosphorylation and sequestration in the cytoplasm, preventing the formation of ATM nuclear foci on irradiation-induced damage. In contrast, the activation of PARP did not seem to alter its ability to form DNA repair foci, but prevented 53BP1 and XRCC4 recruitment at the damage sites. In the nucleus, AsiDNA is essentially associated with DNA-PK, which triggers its activation leading to phosphorylation of H2AX all over chromatin. This pan-nuclear phosphorylation of H2AX correlates with the massive inhibition, at damage sites induced by irradiation, of the recruitment of repair enzymes involved in DSB repair by homologous recombination and nonhomologous end joining. These results highlight the interest in a new generation of DNA repair inhibitors targeting DNA damage signaling.

Details

Title
Inhibition of DNA Repair by Inappropriate Activation of ATM, PARP, and DNA-PK with the Drug Agonist AsiDNA
Author
Berthault, Nathalie 1 ; Bergam, Ptissam 2   VIAFID ORCID Logo  ; Pereira, Floriane 1 ; Girard, Pierre-Marie 1   VIAFID ORCID Logo  ; Dutreix, Marie 1 

 Institut Curie, PSL Research University, CNRS, INSERM, UMR 3347, 91405 Orsay, France; [email protected] (N.B.); [email protected] (F.P.); [email protected] (P.-M.G.); Université Paris-Saclay, CNRS, UMR 3347, 91405 Orsay, France 
 Institut Curie, PSL Research University, CNRS, INSERM, UMS 2016, Multimodal Imaging Centre, 91405 Orsay, France; [email protected]; Université Paris-Saclay, CNRS, UMS 2016, 91405 Orsay, France 
First page
2149
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20734409
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2693959905
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.