CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations
Open accessAbstract
CRISPR-Cas9 is a promising technology for genome editing. Here we use Cas9 nuclease-induced double-strand break DNA (DSB) at the UROS locus to model and correct congenital erythropoietic porphyria. We demonstrate that homology-directed repair is rare compared with NHEJ pathway leading to on-target indels and causing unwanted dysfunctional protein. Moreover, we describe unexpected chromosomal truncations resulting from only one Cas9 nuclease-induced DSB in cell lines and primary cells by a p53-dependent mechanism. Altogether, these side effects may limit the promising perspectives of the CRISPR-Cas9 nuclease system for disease modeling and gene therapy. We show that the single nickase approach could be safer since it prevents on- and off-target indels and chromosomal truncations. These results demonstrate that the single nickase and not the nuclease approach is preferable, not only for modeling disease but also and more importantly for the safe management of future CRISPR-Cas9-mediated gene therapies.
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Substantial deletions or rearrangements of chromosomes have also been observed in CRISPR editing due to repairs facilitated by mechanisms such as homology-directed repair or single-strand annealing within cells.
“Nonetheless, substantial deletions or rearrangements of chromosomes have also been observed in CRISPR editing due to repairs facilitated by mechanisms such as homology-directed repair or single-strand annealing within cells.”
From Machine learning-based prediction models to guide the selection of Cas9 variants for efficient gene editing (2024) · cites this paper as [55]
The Results section (‘Cas9 nuclease induces unwanted chromosomal truncations’; page unavailable) reports megabase-scale terminal deletions and a large duplication after CRISPR-Cas9 editing. It attributes the damage to a nuclease-induced double-strand break, but does not establish that homology-directed repair or single-strand annealing caused it. The Results section on nickase use instead reports HDR without detectable chromosomal truncations. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCullot et al. did not see the same effect in human foreskin fibroblasts, but knocking out TP53 in these primary cells increased large deletion events by 10-fold.
“In fact, they did not see the same effect in human foreskin fibroblasts but knocking-out of TP53 in these primary cells increased the large deletion events by 10-fold (13).”
From Frequent loss of heterozygosity in CRISPR-Cas9–edited early human embryos (2021) · cites this paper as [13]
The Results section reports no detectable increase in chromosomal truncations in fresh or hTERT-immortalized human foreskin fibroblasts, and an increase of up to 10-fold after TP53 knockout. The qualification is that the TP53-knockout experiment used hTERT-immortalized fibroblasts, not fresh primary cells as the citing sentence implies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredRepair of DSBs introduced by Cas9 has been shown to be error prone and may result in complex rearrangements, including chromothripsis, at the site of repair.
“The repair of DSBs introduced by Cas9 has been shown to be error prone and may result in complex rearrangements, including chromothripsis, at the site of repair25–27.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [25]
The Introduction describes double-strand break repair by error-prone NHEJ, and the Results section ‘Cas9 nuclease induces unwanted chromosomal truncations’ reports megabase-scale deletion and gain beginning at a Cas9-induced break. Those findings support error-prone repair and substantial chromosomal damage, but our copy does not identify chromothripsis; a search for that term returned no matching passage. No page numbers were provided. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCullot et al. suggest that CRISPR-Cas9 can induce mega-base scale chromosomal truncations (~10% increase compared to controls).
“Their experiments suggest that CRISPR-Cas9 can induce mega-base scale chromosomal truncations (~10% increase compared to controls).”
From Frequent loss of heterozygosity in CRISPR-Cas9–edited early human embryos (2021) · cites this paper as [13]
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Development and application of prime editing in plants
Tingting, L., Jinpeng, Z., Xi, Y., Kejian, W., Yuchun, R., & Chun, W. (2023) · Rice Science · doi:10.1016/j.rsci.2023.07.005 · Cited by 21 · see citing works
- Authors
- Cullot, G., Boutin, J., Toutain, J., Prat, F., Pennamen, P., Rooryck, C., Teichmann, M., Rousseau, E., Lamrissi-Garcia, I., Guyonnet-Duperat, V., Bibeyran, A., Lalanne, M., Prouzet-Mauléon, V., Turcq, B., Ged, C., Blouin, J.-M., Richard, E., Dabernat, S., Moreau-Gaudry, F., & Bedel, A.
- Affiliations
- Université de Bordeaux (FR)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Inserm (FR)
- ORCID
- Venue
- Nature Communications
- Published
- 2019-03-08
- Volume
- 10
- Issue
- 1
- Pages
- 1136-1136
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6408493
- OpenAlex
- W2919006054
- Cited by
- 474
- References
- 66
- Citations by year
- 2026: 65 · 2025: 63 · 2024: 82 · 2023: 72 · 2022: 65 · 2021: 59 · 2020: 51 · 2019: 16 · 2018: 1
- FWCI
- 15.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-11-LABX-0051)
- Institut National de la Santé et de la Recherche Médicale (U1218)
- Institut Bergonié
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- CRISPR/Cas9 genome editing, DNA double-strand breaks, congenital erythropoietic porphyria, homology-directed repair, non-homologous end joining, indels, off-target effects, gene therapy safety, disease modeling
- MeSH terms
- Gene Editing, CRISPR-Associated Protein 9, RNA, Guide, CRISPR-Cas Systems, Chromosome Deletion, Chromosomes, Human, Pair 10, Deoxyribonuclease I, DNA, Fibroblasts, Humans, Models, Biological, Uroporphyrinogen III Synthetase, Genetic Therapy, Genome, Human, Tumor Suppressor Protein p53, Porphyria, Erythropoietic, K562 Cells, DNA Breaks, Double-Stranded, HEK293 Cells, High-Throughput Nucleotide Sequencing, Recombinational DNA Repair, Primary Cell Culture, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems
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