Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations.

Date publication

novembre 2025

Journal

Nature biotechnology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr CULLOT Grégoire

Tous les auteurs :
Cullot G, Aird EJ, Schlapansky MF, Yeh CD, van de Venn L, Vykhlyantseva I, Kreutzer S, Mailänder D, Lewków B, Klermund J, Montellese C, Biserni M, Aeschimann F, Vonarburg C, Gehart H, Cathomen T, Corn JE

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39604565

Résumé

The DNA-PKcs inhibitor AZD7648 enhances CRISPR-Cas9-directed homology-directed repair efficiencies, with potential for clinical utility, but its possible on-target consequences are unknown. We found that genome editing with AZD7648 causes frequent kilobase-scale and megabase-scale deletions, chromosome arm loss and translocations. These large-scale chromosomal alterations evade detection through typical genome editing assays, prompting caution in deploying AZD7648 and reinforcing the need to investigate multiple types of potential editing outcomes.

Mots clés

Gene Editing, methods, Humans, DNA-Activated Protein Kinase, antagonists & inhibitors, Pyrazoles, pharmacology, CRISPR-Cas Systems, genetics, Recombinational DNA Repair, drug effects, Protein Kinase Inhibitors, pharmacology, Pyrimidines

Référence

Nat Biotechnol. 2025 11;43(11):1778-1782