Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing
Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing
Genome editing has promising therapeutic potential for genetic diseases and cancer (1, 2). However, the most practicable current approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of structural chromosomal abnormalities. Here, we show that a catastrophic mutational process called chromothripsis is a previously unappreciated consequence of CRISPR-Cas9-mediated DSBs. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer (3–6). Using model cell systems and a genome editing protocol similar to ones in clinical trials (7) (NCT03655678, NCT03745287) we show that CRISPR-Cas9-mediated DNA breaks generate abnormal nuclear structures—micronuclei and chromosome bridges—that trigger chromothripsis. Chromothripsis is an on-target toxicity that may be minimized by cell manipulation protocols or screening but cannot be completely avoided in many genome editing applications.
Weiss Mitchell J.、Papathanasiou Stamatis、Zhang Cheng-Zhong、Doerfler Phillip A.、Pellman David、Leibowitz Mitchell L.、Blaine Logan J.、Yao Yu
Department of Hematology, St. Jude Children?ˉs Research HospitalDepartment of Cell Biology, Blavatnik Institute, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer InstituteDepartment of Biomedical Informatics, Harvard Medical School||Department of Data Sciences, Dana-Farber Cancer InstituteDepartment of Hematology, St. Jude Children?ˉs Research HospitalHoward Hughes Medical Institute||Department of Cell Biology, Blavatnik Institute, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer InstituteHoward Hughes Medical Institute||Department of Cell Biology, Blavatnik Institute, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer InstituteDepartment of Cell Biology, Blavatnik Institute, Harvard Medical School||Department of Pediatric Oncology, Dana-Farber Cancer InstituteDepartment of Hematology, St. Jude Children?ˉs Research Hospital
基础医学生物科学研究方法、生物科学研究技术遗传学
ChromothripsisCRISPRCas9Gene editingMicronuclei
Weiss Mitchell J.,Papathanasiou Stamatis,Zhang Cheng-Zhong,Doerfler Phillip A.,Pellman David,Leibowitz Mitchell L.,Blaine Logan J.,Yao Yu.Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing[EB/OL].(2025-03-28)[2025-08-11].https://www.biorxiv.org/content/10.1101/2020.07.13.200998.点此复制
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