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CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations.

Abstract：

: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.

journal_name

Nat Commun

journal_title

Nature communications

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 JM,Richard E,Dabernat S,Moreau-Gaudry F,

doi

10.1038/s41467-019-09006-2

subject

Has Abstract

pub_date

2019-03-08 00:00:00

pages

1136

issue

1

issn

2041-1723

pii

10.1038/s41467-019-09006-2

journal_volume

10

pub_type

杂志文章

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