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

IF 33.1 1区生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Nature biotechnology Pub Date : 2024-11-27 DOI:10.1038/s41587-024-02488-6

Grégoire Cullot, Eric J. Aird, Moritz F. Schlapansky, Charles D. Yeh, Lilly van de Venn, Iryna Vykhlyantseva, Susanne Kreutzer, Dominic Mailänder, Bohdan Lewków, Julia Klermund, Christian Montellese, Martina Biserni, Florian Aeschimann, Cédric Vonarburg, Helmuth Gehart, Toni Cathomen, Jacob E. Corn

引用次数: 0

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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使用 HDR 增强 DNA-PKcs 抑制剂 AZD7648 进行基因组编辑会导致大规模基因组改变

DNA-PKcs抑制剂AZD7648能提高CRISPR-Cas9引导的同源定向修复效率，具有临床应用潜力，但其可能造成的靶上后果尚不清楚。我们发现，用AZD7648进行基因组编辑会导致频繁的千碱基级和兆碱基级缺失、染色体臂缺失和易位。这些大规模的染色体改变无法通过典型的基因组编辑检测方法检测出来，这促使我们在使用 AZD7648 时要谨慎，并加强了研究多种类型的潜在编辑结果的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature biotechnology 工程技术-生物工程与应用微生物

CiteScore

63.00

自引率

1.70%

发文量

382

审稿时长

3 months

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