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Global detection of DNA repair outcomes induced by CRISPR-Cas9

Mengzhu Liu, Weiwei Zhang, Changchang Xin, Jianhang Yin, Yafang Shang, Chen Ai, Jiaxin Li, Fei-long Meng, View ORCID ProfileJiazhi Hu
doi: https://doi.org/10.1101/2021.02.15.431335
Mengzhu Liu
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Weiwei Zhang
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Changchang Xin
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Jianhang Yin
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Yafang Shang
2State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
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Chen Ai
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Jiaxin Li
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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Fei-long Meng
2State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China
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Jiazhi Hu
1The MOE Key Laboratory of Cell Proliferation and Differentiation, Genome Editing Research Center, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
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  • ORCID record for Jiazhi Hu
  • For correspondence: hujz@pku.edu.cn
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Abstract

CRISPR-Cas9 generates double-stranded DNA breaks (DSBs) to activate cellular DNA repair pathways for genome editing. The repair of DSBs leads to small insertions or deletions (indels) and other complex byproducts, including large deletions and chromosomal translocations. Indels are well understood to disrupt target genes, while the other deleterious byproducts remain elusive. We developed a new in silico analysis pipeline for the previously described primer-extension-mediated sequencing assay to comprehensively characterize CRISPR-Cas9-induced DSB repair outcomes in human or mouse cells. We identified tremendous deleterious DSB repair byproducts of CRISPR-Cas9 editing, including large deletions, plasmid integrations, and chromosomal translocations. We further elucidated the important roles of microhomology, chromosomal interaction, recurrent DSBs, and DSB repair pathways in the generation of these byproducts. Our findings provide an extra dimension for genome editing safety besides off-targets. And caution should be exercised to avoid not only off-target damages but also deleterious DSB repair byproducts during genome editing.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 16, 2021.
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Global detection of DNA repair outcomes induced by CRISPR-Cas9
Mengzhu Liu, Weiwei Zhang, Changchang Xin, Jianhang Yin, Yafang Shang, Chen Ai, Jiaxin Li, Fei-long Meng, Jiazhi Hu
bioRxiv 2021.02.15.431335; doi: https://doi.org/10.1101/2021.02.15.431335
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Global detection of DNA repair outcomes induced by CRISPR-Cas9
Mengzhu Liu, Weiwei Zhang, Changchang Xin, Jianhang Yin, Yafang Shang, Chen Ai, Jiaxin Li, Fei-long Meng, Jiazhi Hu
bioRxiv 2021.02.15.431335; doi: https://doi.org/10.1101/2021.02.15.431335

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