A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing

Recent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framew...

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Veröffentlicht in:Nature communications Jg. 12; H. 1; S. 6512 - 13
Hauptverfasser: Sinha, Sanju, Barbosa, Karina, Cheng, Kuoyuan, Leiserson, Mark D. M., Jain, Prashant, Deshpande, Anagha, Wilson, David M., Ryan, Bríd M., Luo, Ji, Ronai, Ze’ev A., Lee, Joo Sang, Deshpande, Aniruddha J., Ruppin, Eytan
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 11.11.2021
Nature Publishing Group
Nature Portfolio
Schlagworte:
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Cancer
Computational Biology
Computer applications
CRISPR
CRISPR-Associated Protein 9 - genetics
CRISPR-Associated Protein 9 - metabolism
Damage
DNA damage
Gene Editing - methods
Gene mapping
Genetic modification
Genome editing
Genomes
Humanities and Social Sciences
Humans
multidisciplinary
Mutants
Mutation
Mutation - genetics
p53 Protein
Proto-Oncogene Proteins p21(ras) - genetics
Proto-Oncogene Proteins p21(ras) - metabolism
Science
Science (multidisciplinary)
ISSN:2041-1723, 2041-1723
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Zusammenfassung:Recent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53 , wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS -mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations. CRISPR-Cas9 gene editing can induce a p53 mediated damage response. Here the authors investigate the possibility of selection of pre-existing cancer driver mutations during CRISPR-Cas9 knockout based gene editing and identify KRAS mutants that may confer a selected advantage to edited cells.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-26788-6