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.

中文翻译：

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

DNA-PKcs 抑制剂AZD7648可增强 CRISPR-Cas9 导向的同源导向修复效率，具有潜在的临床应用，但其可能的靶向后果尚不清楚。我们发现，使用 AZD7648 进行基因组编辑会导致频繁的千碱基和兆碱基尺度缺失、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分析逃避检测，促使谨慎部署AZD7648并加强了研究多种类型潜在编辑结果的必要性。