Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations
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.
Authors
- Helmuth Gehart (ORCID: https://orcid.org/0000-0002-9165-5824)
- Eric J. Aird (ORCID: https://orcid.org/0000-0002-4873-042X)
- Florian Aeschimann (ORCID: https://orcid.org/0000-0001-5213-034X)
- Grégoire Cullot (ORCID: https://orcid.org/0000-0003-3925-705X)
- Christian Montellese (ORCID: https://orcid.org/0009-0009-4261-088X)
- Lilly van de Venn (ORCID: https://orcid.org/0000-0003-0158-1225)
- Julia Klermund (ORCID: https://orcid.org/0000-0001-6069-8189)
- Martina Biserni (ORCID: https://orcid.org/0000-0002-3641-4665)
- Moritz F. Schlapansky (ORCID: https://orcid.org/0000-0001-6072-7840)
- Cédric Vonarburg (ORCID: https://orcid.org/0000-0001-8074-1877)
- Bohdan Lewków
- Susanne Kreutzer (ORCID: https://orcid.org/0000-0001-6286-534X)
- Jacob E. Corn (ORCID: https://orcid.org/0000-0002-7798-5309)
- Charles D. Yeh (ORCID: https://orcid.org/0000-0002-2707-6035)
- Toni Cathomen (ORCID: https://orcid.org/0000-0002-7757-4630)
- Iryna Vykhlyantseva
- Dominic Mailänder
Institutions
- Swissmedic (CH)
- University of Freiburg (DE)
- ETH Zurich (CH)
- CSL (Switzerland) (CH)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2024-11-27
- DOI
- https://doi.org/10.1038/s41587-024-02488-6
- Citations
- 56
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 13.09
Funders
- Deutsche Forschungsgemeinschaft
- Horizon 2020 Framework Programme