Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing.

Autor: Leibowitz ML; Howard Hughes Medical Institute, Chevy Chase, MD, USA.; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Papathanasiou S; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Doerfler PA; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Blaine LJ; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Sun L; Single-Cell Sequencing Program, Dana-Farber Cancer Institute, Boston, MA, USA., Yao Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang CZ; Department of Biomedical Informatics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA., Weiss MJ; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. mitch.weiss@stjude.org., Pellman D; Howard Hughes Medical Institute, Chevy Chase, MD, USA. david_pellman@dfci.harvard.edu.; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. david_pellman@dfci.harvard.edu.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. david_pellman@dfci.harvard.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2021 Jun; Vol. 53 (6), pp. 895-905. Date of Electronic Publication: 2021 Apr 12.
DOI: 10.1038/s41588-021-00838-7
Abstrakt: 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.
Databáze: MEDLINE
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