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...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 12; no. 1; pp. 6512 - 13
Main Authors: 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
Language:English
Published: London Nature Publishing Group UK 11.11.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography: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