使用增强同源定向修复（HDR）的DNA依赖蛋白激酶催化亚基（DNA-PKcs）抑制剂AZD7648进行基因组编辑会导致大规模基因组改变。
Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations.
作者信息
Cullot Grégoire, Aird Eric J, Schlapansky Moritz F, Yeh Charles D, van de Venn Lilly, Vykhlyantseva Iryna, Kreutzer Susanne, Mailänder Dominic, Lewków Bohdan, Klermund Julia, Montellese Christian, Biserni Martina, Aeschimann Florian, Vonarburg Cédric, Gehart Helmuth, Cathomen Toni, Corn Jacob E
机构信息
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg, Freiburg, Germany.
出版信息
Nat Biotechnol. 2024 Nov 27. doi: 10.1038/s41587-024-02488-6.
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.
DNA依赖蛋白激酶催化亚基（DNA-PKcs）抑制剂AZD7648可提高CRISPR-Cas9介导的同源定向修复效率，具有临床应用潜力，但其可能的靶向效应尚不清楚。我们发现，使用AZD7648进行基因组编辑会导致频繁的千碱基规模和兆碱基规模的缺失、染色体臂丢失和易位。这些大规模的染色体改变通过典型的基因组编辑检测方法难以检测到，这提示在应用AZD7648时需谨慎，并进一步强调了研究多种潜在编辑结果的必要性。
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