期刊
NATURE GENETICS
卷 53, 期 6, 页码 895-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-021-00838-7
关键词
-
资金
- National Science Foundation Graduate Research Fellowship [DGE1144152]
- National Cancer Institute [K22CA216319]
- Howard Hughes Medical Institute
- NIH [P30 CA21765, R01 CA213404, F32 DK118822, P01 HL053749]
- Assisi Foundation
- Doris Duke Charitable Foundation
- St. Jude/ALSAC
CRISPR-Cas9 editing can result in nuclear structural defects, formation of micronuclei and chromosome bridges, leading to a mutational process known as chromothripsis. Chromothripsis, extensive chromosome rearrangement restricted to one or a few chromosomes, can cause human congenital disease and cancer. The potential for extensive chromosomal rearrangements should be considered and monitored as genome editing is implemented in the clinic.
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. 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据