Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing
Nature genetics, 2021•nature.com
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 …
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 …
Abstract
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.
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