ArticleProtein & cell2020
CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway.
Article in Protein & cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 52 citations in OpenAlex.
- Enhancing the specificity of gene editing outcomes by using Cas9 variants in porcine embryos.Journal of animal science · 2026Article
- Improved vectors for retron-mediated CRISPR-Cas9 genome editing in Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2025Article
- Epigenetic Regulation of Aging and its Rejuvenation.MedComm · 2025Review
- Mismatch prime editing gRNA increased efficiency and reduced indels.Nature communications · 2025Article
- Article
- In vivo evaluation of guide-free Cas9-induced safety risks in a pig model.Signal transduction and targeted therapy · 2024Article
- Unexpected mutations occurred in CRISPR/Cas9 edited Drosophila analyzed by deeply whole genomic sequencing.Heliyon · 2024Article
- CRISPR-Cas13a Targeting the FGFR3-TACC3 Fusion Gene Inhibits Proliferation of Bladder Cancer Cells in vitro and in vivo.OncoTargets and therapy · 2024Article
- Breaking genetic shackles: The advance of base editing in genetic disorder treatment.Frontiers in pharmacology · 2024Review
- Evaluation of guide-free Cas9-induced genomic damage and transcriptome changes in pig embryos.Molecular therapy. Nucleic acids · 2023Article
- Engineering of cytosine base editors with DNA damage minimization and editing scope diversification.Nucleic acids research · 2023Article
- Base editors: development and applications in biomedicine.Frontiers of medicine · 2023Review
- Doxycycline-dependent Cas9-expressing pig resources for conditional in vivo gene nullification and activation.Genome biology · 2023Article
- Current understanding of osteoarthritis pathogenesis and relevant new approaches.Bone research · 2022Review
- Recent progress of the tumor microenvironmental metabolism in cervical cancer radioresistance.Frontiers in oncology · 2022Review
- Advances in CRISPR/Cas9.BioMed research international · 2022Review
- Tips, Tricks, and Potential Pitfalls of CRISPR Genome Editing inFrontiers in bioengineering and biotechnology · 2022Review
- Adenine base-editing-mediated exon skipping induces gene knockout in cultured pig cells.Biotechnology letters · 2022Article
- Application of the modified cytosine base-editing in the cultured cells of bama minipig.Biotechnology letters · 2021Article
- Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
With its high efficiency for site-specific genome editing and easy manipulation, the clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (CAS9) system has become the most widely used gene editing technology in biomedical research. In addition, significant progress has been made for the clinical development of CRISPR/CAS9 based gene therapies of human diseases, several of which are entering clinical trials. Here we report that CAS9 protein can function as a genome mutator independent of any exogenous guide RNA (gRNA) in human cells, promoting genomic DNA double-stranded break (DSB) damage and genomic instability. CAS9 interacts with the KU86 subunit of the DNA-dependent protein kinase (DNA-PK) complex and disrupts the interaction between KU86 and its kinase subunit, leading to defective DNA-PK-dependent repair of DNA DSB damage via non-homologous end-joining (NHEJ) pathway. XCAS9 is a CAS9 variant with potentially higher fidelity and broader compatibility, and dCAS9 is a CAS9 variant without nuclease activity. We show that XCAS9 and dCAS9 also interact with KU86 and disrupt DNA DSB repair. Considering the critical roles of DNA-PK in maintaining genomic stability and the pleiotropic impact of DNA DSB damage responses on cellular proliferation and survival, our findings caution the interpretation of data involving CRISPR/CAS9-based gene editing and raise serious safety concerns of CRISPR/CAS9 system in clinical application.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.