Cited by 365CRISPR and Genetic EngineeringRNA regulation and diseaseRNA Interference and Gene Delivery

CRISPR-Mediated Base Editing Enables Efficient Disruption of Eukaryotic Genes through Induction of STOP Codons

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Billon, Pierre, Bryant, Eric E., Joseph, Sarah A., Nambiar, Tarun S., Hayward, Samuel B., Rothstein, Rodney, Ciccia, Alberto·2017·Molecular Cell

Abstract

Standard CRISPR-mediated gene disruption strategies rely on Cas9-induced DNA double-strand breaks (DSBs). Here, we show that CRISPR-dependent base editing efficiently inactivates genes by precisely converting four codons (CAA, CAG, CGA, and TGG) into STOP codons without DSB formation. To facilitate gene inactivation by induction of STOP codons (iSTOP), we provide access to a database of over 3.4 million single guide RNAs (sgRNAs) for iSTOP (sgSTOPs) targeting 97%-99% of genes in eight eukaryotic species, and we describe a restriction fragment length polymorphism (RFLP) assay that allows the rapid detection of iSTOP-mediated editing in cell populations and clones. To simplify the selection of sgSTOPs, our resource includes annotations for off-target propensity, percentage of isoforms targeted, prediction of nonsense-mediated decay, and restriction enzymes for RFLP analysis. Additionally, our database includes sgSTOPs that could be employed to precisely model over 32,000 cancer-associated nonsense mutations. Altogether, this work provides a comprehensive resource for DSB-free gene disruption by iSTOP.

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  • Base editing can be repurposed as a gene loss of function tool by creating a stop codon or a gene knockdown by creating an upstream open reading frame (uORF).

    “It can also be repurposed as a gene loss of function tool by creating a stop codon or a gene knockdown by creating an upstream open reading frame (uORF) (Billon et al., 2017;Kuscu et al., 2017;Xiong et al., 2022).”

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Authors
Billon, P., Bryant, E. E., Joseph, S. A., Nambiar, T. S., Hayward, S. B., Rothstein, R., & Ciccia, A.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Columbia University (US)
Corresponding author
Ciccia, Alberto
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2017-09
Volume
67
Issue
6
Pages
1068-1079.e4
ISSN
1097-2765 (ISSN-L)
OpenAlex
W2752453466
Cited by
363
References
50
Citations by year
2026: 28 · 2025: 25 · 2024: 27 · 2023: 36 · 2022: 41 · 2021: 46 · 2020: 65 · 2019: 48 · 2018: 42 · 2017: 3
FWCI
17.77
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (T32CA009503, T32GM008798, R01CA197774, R01GM117064, R35GM118180)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
CRISPR base editing, gene inactivation, nonsense mutation, nonsense-mediated mRNA decay, cancer-associated mutations
MeSH terms
Gene Editing, RNA, Guide, CRISPR-Cas Systems, Animals, DNA Restriction Enzymes, Humans, Neoplasms, Polymorphism, Restriction Fragment Length, Saccharomyces cerevisiae, Transfection, Gene Expression Regulation, Fungal, Gene Expression Regulation, Neoplastic, Arabidopsis, RNA, Guide, Kinetoplastida, Codon, Terminator, Codon, Nonsense, Gene Expression Regulation, Plant, Computational Biology, Gene Silencing, Databases, Genetic, Mice, Rats, HEK293 Cells, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, CRISPR-Associated Proteins

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