Targeted Chromosomal Cleavage and Mutagenesis in Drosophila Using Zinc-Finger Nucleases
Abstract
Zinc-finger nucleases (ZFNs) are hybrids between a nonspecific DNA-cleavage domain and a DNA-binding domain composed of Cys2His2 zinc fingers. Because zinc fingers can be manipulated to recognize a broad range of sequences, these enzymes have the potential to direct cleavage to arbitrarily chosen targets. We have tested this idea by designing a pair of ZFNs that recognize a unique site in the yellow (y) gene of Drosophila. When these nucleases were expressed in developing larvae, they led to somatic mutations specifically in the y gene. These somatic mosaics were observed in approximately one-half of the males expressing both nucleases. Germline y mutations were recovered from 5.7% of males, but from none of the females, tested. DNA sequences were determined and showed that all of the mutations were small deletions and/or insertions located precisely at the designed target. These are exactly the types of alterations expected from nonhomologous end joining (NHEJ) following double-strand cleavage of the target. This approach promises to permit generation of directed mutations in many types of cells and organisms.
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NHEJ repairs double-stranded breaks without a homologous DNA template, regularly leading to mutations and deletions, and is error-prone.
“In NHEJ, protein factors re-ligate the broken DNA strand either directly or by including nucleotide insertions or deletions (indels) (Hefferin & Tomkinson, 2005). This process occurs without a homologous DNA template, regularly leading to mutations and deletions in the repaired strand (Bibikova et al., 2002), as shown in Figure 1(A). NHEJ is, therefore, characterized as error-prone.”
From Delivering CRISPR: a review of the challenges and approaches (2018) · cites this paper as Bibikova et al., 2002
If nuclease action mutates unintended targets that are important for cellular physiology, the treated cells may become dysfunctional or even die.
“For example, if the nuclease action mutates unintended targets that are important for cellular physiology, the treated cells may become dysfunctional or even die [61,62,63].”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [61]
The fundamental safety concern for using ZFN mediated gene disruption for human therapy is the specificity of gene targeting.
“The fundamental safety concern for using ZFN mediated gene disruption for human therapy is the specificity of gene targeting.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [61]
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- Authors
- Bibikova, M., Golic, M., Golic, K. G., & Carroll, D.
- Affiliations
- University of Utah (US)
- Corresponding author
- Carroll, Dana
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2002-07-01
- Volume
- 161
- Issue
- 3
- Pages
- 1169-1175
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- OpenAlex
- W1906155566
- Cited by
- 860
- References
- 50
- Citations by year
- 2026: 12 · 2025: 30 · 2024: 44 · 2023: 40 · 2022: 50 · 2021: 46 · 2020: 42 · 2019: 41 · 2018: 49 · 2017: 50 · 2016: 70 · 2015: 64 · 2014: 65 · 2013: 47 · 2012: 45
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01gm060700-12)
- National Institute of General Medical Sciences (R01GM60700, R01 GM58504, R01GM058504)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- zinc finger nucleases, targeted mutagenesis, Drosophila, yellow gene, germline mutations, non-homologous end joining, double-strand DNA cleavage, C2H2 zinc finger, directed mutagenesis
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Crosses, Genetic, Deoxyribonucleases, DNA Transposable Elements, Drosophila, Female, Genetic Vectors, Male, Ribonucleases, Transformation, Genetic, Mutagenesis, Insertional, Zinc Fingers
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