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

Mitchell L Leibowitz1,2,3, Stamatis Papathanasiou2,3, Phillip A Doerfler4

  • 1Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Nature Genetics
|April 13, 2021
PubMed

Insights

CRISPR-Cas9 genome editing can cause dangerous DNA double-strand breaks, leading to chromothripsis, a major cause of cancer and congenital diseases. This study reveals chromothripsis as an unappreciated on-target risk of CRISPR-Cas9 editing that requires clinical monitoring.

Area of Science:

  • Molecular Biology
  • Genetics
  • Genomics

Background:

  • Genome editing holds promise for treating genetic diseases and cancer.
  • Current methods often induce DNA double-strand breaks (DSBs), potentially causing chromosomal abnormalities.

Purpose of the Study:

  • To investigate the chromosomal consequences of CRISPR-Cas9 genome editing.
  • To identify if CRISPR-Cas9-induced DSBs lead to chromothripsis.

Main Methods:

  • Utilized model cells and single-cell whole-genome sequencing.
  • Performed editing at a clinically relevant locus in relevant cells.

Main Results:

  • CRISPR-Cas9 editing induced nuclear structural defects, micronuclei, and chromosome bridges.
  • These defects initiated chromothripsis, a process of extensive chromosomal rearrangement.
  • Chromothripsis was identified as an on-target consequence of CRISPR-Cas9-generated DSBs.

Conclusions:

  • Chromothripsis is a previously unrecognized on-target outcome of CRISPR-Cas9 editing.
  • The potential for chromosomal rearrangements must be considered and monitored during clinical genome editing applications.

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