Journal or Publishing Institution: Nature genetics
Study: https://www.nature.com/articles/s41588-021-00838-7
Author(s): Leibowitz, M.L., Papathanasiou, S., Doerfler, P.A., Blaine, L.J., Sun, L., Yao, Y., Zhang, C.Z., Weiss, M.J. and Pellman, D.
Article Type: Peer Reviewed Study
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.
Keywords: Chromothripsis, CRISPR–Cas9, genome editing
Citation:
Leibowitz, M.L., Papathanasiou, S., Doerfler, P.A., Blaine, L.J., Sun, L., Yao, Y., Zhang, C.Z., Weiss, M.J. and Pellman, D., 2021. Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing. Nature genetics, 53(6), pp.895-905.
Record ID: 2583
