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Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
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Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
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Journal Article
Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
2021
Overview
Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR–Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that chromothripsis is a previously unappreciated on-target consequence of CRISPR–Cas9-generated DSBs. As genome editing is implemented in the clinic, the potential for extensive chromosomal rearrangements should be considered and monitored.
Chromothripsis, a chromosomal shattering event, can be elicited by micronuclei and chromosome bridges formed by CRISPR–Cas9-generated double-stranded breaks. Extensive chromosomal rearrangements may thus be an on-target effect of genome editing.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 14/63
/ 45/23
/ 631/208
/ 631/80
/ Anemia, Sickle Cell - genetics
/ Animal Genetics and Genomics
/ Biomedical and Life Sciences
/ Cancer
/ Chromosomes, Human - genetics
/ CRISPR
/ CRISPR-Associated Protein 9 - metabolism
/ CRISPR-Cas Systems - genetics
/ DNA
/ Editing
/ Genes
/ Genomes
/ Human chromosome abnormalities
/ Humans
/ Micronucleus, Germline - genetics
