• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

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.

DOI:10.1038/s41587-024-02488-6
PMID:39604565
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.

摘要

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。

相似文献

1
Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations.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。
Nat Biotechnol. 2024 Nov 27. doi: 10.1038/s41587-024-02488-6.
2
DNA-PK inhibition enhances gene editing efficiency in HSPCs for CRISPR-based treatment of X-linked hyper IgM syndrome.DNA依赖性蛋白激酶（DNA-PK）抑制可提高造血干细胞（HSPCs）中的基因编辑效率，用于基于CRISPR的X连锁高免疫球蛋白M综合征治疗。
Mol Ther Methods Clin Dev. 2024 Jul 27;32(3):101297. doi: 10.1016/j.omtm.2024.101297. eCollection 2024 Sep 12.
3
AZD7648 (DNA-PKcs inhibitor): a two-edged sword for editing genomes.AZD7648（DNA依赖性蛋白激酶催化亚基抑制剂）：基因组编辑的双刃剑。
Funct Integr Genomics. 2025 Mar 1;25(1):49. doi: 10.1007/s10142-025-01560-x.
4
High-efficiency transgene integration by homology-directed repair in human primary cells using DNA-PKcs inhibition.利用 DNA-PKcs 抑制实现人原代细胞中同源定向修复的高效转基因整合。
Nat Biotechnol. 2024 May;42(5):731-744. doi: 10.1038/s41587-023-01888-4. Epub 2023 Aug 3.
5
Rapid genome editing by CRISPR-Cas9-POLD3 fusion.CRISPR-Cas9-POLD3 融合的快速基因组编辑。
Elife. 2021 Dec 13;10:e75415. doi: 10.7554/eLife.75415.
6
DNA-PKcs inhibition improves sequential gene insertion of the full-length cDNA in airway stem cells.DNA依赖性蛋白激酶催化亚基（DNA-PKcs）抑制作用可改善气道干细胞中全长互补DNA（cDNA）的序列基因插入。
Mol Ther Nucleic Acids. 2024 Sep 16;35(4):102339. doi: 10.1016/j.omtn.2024.102339. eCollection 2024 Dec 10.
7
CRISPR-Cas9-mediated homology-directed repair for precise gene editing.用于精确基因编辑的CRISPR-Cas9介导的同源定向修复
Mol Ther Nucleic Acids. 2024 Sep 26;35(4):102344. doi: 10.1016/j.omtn.2024.102344. eCollection 2024 Dec 10.
8
Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing.同时抑制 DNA-PK 和 Polϴ 可提高基因组编辑的整合效率和精度。
Nat Commun. 2023 Aug 14;14(1):4761. doi: 10.1038/s41467-023-40344-4.
9
DNA-PKcs Inhibition Improves Sequential Gene Insertion of the Full-Length cDNA in Airway Stem Cells.DNA依赖蛋白激酶催化亚基（DNA-PKcs）抑制作用可改善气道干细胞中全长互补DNA（cDNA）的顺序基因插入。
bioRxiv. 2024 Aug 12:2024.08.12.607571. doi: 10.1101/2024.08.12.607571.
10
Precision genome editing in the CRISPR era.CRISPR时代的精准基因组编辑。
Biochem Cell Biol. 2017 Apr;95(2):187-201. doi: 10.1139/bcb-2016-0137. Epub 2016 Sep 29.

引用本文的文献

1
Targeted DNA ADP-ribosylation triggers templated repair in bacteria and base mutagenesis in eukaryotes.靶向DNA ADP-核糖基化触发细菌中的模板修复和真核生物中的碱基诱变。
Nat Biotechnol. 2025 Sep 4. doi: 10.1038/s41587-025-02802-w.
2
Autologous genome-edited hematopoietic stem cells correct Gaucher disease and establish a platform for clinical translation.自体基因组编辑造血干细胞纠正戈谢病并建立临床转化平台。
Res Sq. 2025 Aug 18:rs.3.rs-7123212. doi: 10.21203/rs.3.rs-7123212/v1.
3
ONE-STEP tagging: a versatile method for rapid site-specific integration by simultaneous reagent delivery.

本文引用的文献

1
On- and off-target effects of paired CRISPR-Cas nickase in primary human cells.成对CRISPR-Cas切口酶在原代人类细胞中的靶向和脱靶效应。
Mol Ther. 2024 May 1;32(5):1298-1310. doi: 10.1016/j.ymthe.2024.03.006. Epub 2024 Mar 7.
2
DNA-PKcs suppresses illegitimate chromosome rearrangements.DNA-PKcs 抑制非同源染色体重排。
Nucleic Acids Res. 2024 May 22;52(9):5048-5066. doi: 10.1093/nar/gkae140.
3
C-to-G editing generates double-strand breaks causing deletion, transversion and translocation.C 到 G 碱基编辑会产生双链断裂，导致缺失、颠换和易位。
一步标记法：一种通过同时递送试剂实现快速位点特异性整合的通用方法。
Nucleic Acids Res. 2025 Aug 11;53(15). doi: 10.1093/nar/gkaf809.
4
Gene editing in hematopoietic stem cells by co-delivery of Cas9/sgRNA ribonucleoprotein and templates for homology-directed repair in 'all-in-one' lentivirus-derived nanoparticles.通过在“一体化”慢病毒衍生纳米颗粒中共递送Cas9/sgRNA核糖核蛋白和同源定向修复模板，对造血干细胞进行基因编辑。
Nucleic Acids Res. 2025 Aug 11;53(15). doi: 10.1093/nar/gkaf767.
5
Targeted gene editing and near-universal cDNA insertion of CYBA and CYBB as a treatment for chronic granulomatous disease.靶向基因编辑以及CYBA和CYBB的近乎普遍的cDNA插入作为慢性肉芽肿病的一种治疗方法。
Nat Commun. 2025 Aug 12;16(1):7475. doi: 10.1038/s41467-025-62738-2.
6
Off-target effects in CRISPR-Cas genome editing for human therapeutics: Progress and challenges.用于人类治疗的CRISPR-Cas基因组编辑中的脱靶效应：进展与挑战。
Mol Ther Nucleic Acids. 2025 Jul 17;36(3):102636. doi: 10.1016/j.omtn.2025.102636. eCollection 2025 Sep 9.
7
The hidden risks of CRISPR/Cas: structural variations and genome integrity.CRISPR/Cas的潜在风险：结构变异与基因组完整性
Nat Commun. 2025 Aug 5;16(1):7208. doi: 10.1038/s41467-025-62606-z.
8
Prime assembly with linear DNA donors enables large genomic insertions.使用线性DNA供体进行的主要组装能够实现大基因组插入。
bioRxiv. 2025 Jun 17:2025.06.16.659978. doi: 10.1101/2025.06.16.659978.
9
Refined DNA repair manipulation enables a universal knock-in strategy in mouse embryos.优化的DNA修复操作可实现小鼠胚胎中的通用敲入策略。
Nat Commun. 2025 Jul 15;16(1):6502. doi: 10.1038/s41467-025-61696-z.
10
Engineering biomimetic bone marrow niche with gene modified mesenchymal stromal cells for ex vivo culture of human hematopoietic stem and progenitor cells.利用基因修饰的间充质基质细胞构建仿生骨髓微环境用于人造血干细胞和祖细胞的体外培养。
Stem Cell Res Ther. 2025 Jul 1;16(1):335. doi: 10.1186/s13287-025-04474-4.
Nat Cell Biol. 2024 Feb;26(2):294-304. doi: 10.1038/s41556-023-01342-2. Epub 2024 Jan 23.
4
Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells.临床 CRISPR-Cas9 基因编辑 T 细胞中染色体丢失的减轻。
Cell. 2023 Oct 12;186(21):4567-4582.e20. doi: 10.1016/j.cell.2023.08.041. Epub 2023 Oct 3.
5
Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing.同时抑制 DNA-PK 和 Polϴ 可提高基因组编辑的整合效率和精度。
Nat Commun. 2023 Aug 14;14(1):4761. doi: 10.1038/s41467-023-40344-4.
6
A novel Cas9 fusion protein promotes targeted genome editing with reduced mutational burden in primary human cells.一种新型 Cas9 融合蛋白可降低原发性人细胞中的突变负担，促进靶向基因组编辑。
Nucleic Acids Res. 2023 May 22;51(9):4660-4673. doi: 10.1093/nar/gkad255.
7
Modulating mutational outcomes and improving precise gene editing at CRISPR-Cas9-induced breaks by chemical inhibition of end-joining pathways.通过化学抑制末端连接途径来调节 CRISPR-Cas9 诱导断裂处的突变结果和提高精确基因编辑。
Cell Rep. 2023 Feb 28;42(2):112019. doi: 10.1016/j.celrep.2023.112019. Epub 2023 Jan 25.
8
Recursive Editing improves homology-directed repair through retargeting of undesired outcomes.递归编辑通过重新定位不理想的结果来改进同源定向修复。
Nat Commun. 2022 Aug 5;13(1):4550. doi: 10.1038/s41467-022-31944-7.
9
Prime editing efficiency and fidelity are enhanced in the absence of mismatch repair.在不存在错配修复的情况下，碱基编辑的效率和保真度得到提高。
Nat Commun. 2022 Feb 9;13(1):760. doi: 10.1038/s41467-022-28442-1.
10
Inference of CRISPR Edits from Sanger Trace Data.从 Sanger 测序数据推断 CRISPR 编辑。
CRISPR J. 2022 Feb;5(1):123-130. doi: 10.1089/crispr.2021.0113. Epub 2022 Feb 2.