Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing.
Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing.
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DOI：
10.1038/s41588-021-00838-7
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发表时间：
2021-06
期刊：
影响因子：
30.8
通讯作者：
Pellman D
中科院分区：
文献类型：
--
作者：
Leibowitz ML;Papathanasiou S;Doerfler PA;Blaine LJ;Sun L;Yao Y;Zhang CZ;Weiss MJ;Pellman D
基因组编辑在治疗遗传病和癌症方面具有治疗潜力。然而，目前最可行的方法依赖于DNA双链断裂(DSB)的产生，这可能导致一系列特征不佳的染色体结构异常。在这里，使用模型细胞和单细胞全基因组测序，以及通过在临床相关细胞中的临床相关位置进行编辑，我们表明CRISPR-Cas9编辑会产生核的结构缺陷-微核和染色体桥-这启动了一种称为染色质的突变过程。染色质疾病是一种广泛的染色体重排，局限于一条或几条染色体，可导致人类先天性疾病和癌症。这些结果表明，嗜铬细胞症是CRISPR-Cas9产生的DSB的一种以前未被认识的靶向后果。随着基因组编辑在临床上的实施，广泛的染色体重排的可能性应该被考虑和监测。
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—that 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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