CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway.
In: Protein & cell, Jg. 11 (2020-05-01), Heft 5, S. 352
Online
academicJournal
Zugriff:
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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CAS9 is a genome mutator by directly disrupting DNA-PK dependent DNA repair pathway.
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Autor/in / Beteiligte Person: | Xu, S ; Kim, J ; Tang, Q ; Chen, Q ; Liu, J ; Xu, Y ; Fu, X |
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Zeitschrift: | Protein & cell, Jg. 11 (2020-05-01), Heft 5, S. 352 |
Veröffentlichung: | 2023- : [Oxford] : Oxford University Press ; <i>Original Publication</i>: Heidelberg : Beijing, China : Springer ; Higher Education Press, 2020 |
Medientyp: | academicJournal |
ISSN: | 1674-8018 (electronic) |
DOI: | 10.1007/s13238-020-00699-6 |
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