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CRISPR–Cas9介导的基因组编辑会导致染色体碎裂
作者:小柯机器人 发布时间:2021/4/16 14:01:56

美国哈佛医学院David Pellman、圣犹大儿童研究医院Mitchell J. Weiss等研究人员合作发现,CRISPR–Cas9介导的基因组编辑会导致染色体碎裂。相关论文于2021年4月12日在线发表在《自然—遗传学》杂志上。

通过使用模型细胞和单细胞全基因组测序,以及在临床相关细胞中的相关位点进行编辑,研究人员证明了CRISPR–Cas9编辑产生了核、微核和染色体桥的结构缺陷,这些缺陷会引发一种称为染色体碎裂的突变过程。染色体碎裂是广泛的染色体重排,仅限于一个或几个染色体,这可能导致人类先天性疾病和癌症。这些结果表明,染色质碎裂是CRISPR–Cas9生成的DNA双链断裂(DSB)以往未检测到的非脱靶结果。由于临床上已进行基因组编辑,因此应考虑并监测广泛染色体重排的可能性。 

据介绍,基因组编辑具有治疗遗传疾病和癌症的治疗潜力。但是,当前最可行的方法依赖于DSB的产生,而DNA双链断裂可能导致染色体结构异常,但对这些异常了解得不多。

附:英文原文

Title: Chromothripsis as an on-target consequence of CRISPR–Cas9 genome editing

Author: Mitchell L. Leibowitz, Stamatis Papathanasiou, Phillip A. Doerfler, Logan J. Blaine, Lili Sun, Yu Yao, Cheng-Zhong Zhang, Mitchell J. Weiss, David Pellman

Issue&Volume: 2021-04-12

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.

DOI: 10.1038/s41588-021-00838-7

Source: https://www.nature.com/articles/s41588-021-00838-7

 

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex