Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 39604565.
- Also identified by DOI 10.1038/s41587-024-02488-6 and PMC identifier 12611759.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Gene Editing
- DNA-Activated Protein Kinase
- Pyrazoles
- Recombinational DNA Repair