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


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Date

2024-11-27

Publication Type

Journal Article

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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.

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published

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09712 - Gehart, Helmuth / Gehart, Helmuth check_circle
09635 - Corn, Jacob / Corn, Jacob check_circle

Notes

Funding

855741 - Dna Damage REsponse: Actionabilities, Maps and Mechanisms (EC)
101070740 - FINE-TUNING T CELL NETWORKS OF EXHAUSTION BY SYNTHETIC SENSORS (SBFI)
101057438/22.00186 - Gene-edited T cells combating IgA Nephropathy. A blueprint approach for safe & efficient genome editing (SBFI)
188858 - Molecular mechanisms of human genome editing (SNF)
227979 - 10001116 - Heterogeneous Editing and RepAir (HERA) (SNF)

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