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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Vydáno v:	Nature communications Ročník 12; číslo 1; s. 6512 - 13
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 11.11.2021 Nature Publishing Group Nature Portfolio
Témata:	13/89 38/23 38/39 38/47 38/71 42/34 45/41 631/114 631/337/4041/3196 631/67 96/63 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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-26788-6