ArticlePLoS genetics2014
The mechanism of gene targeting in human somatic cells.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- SETDB1/ATF7IP regulate the precise genome engineering of HUSH-regulated genes.Epigenetics & chromatin · 2026Article
- Gene editing and CRISPR-dependent homology-mediated end joining.Experimental & molecular medicine · 2025Review
- Cas9-induced targeted integration of large DNA payloads in primary human T cells via homology-mediated end-joining DNA repair.Nature biomedical engineering · 2024Article
- High-efficiency targeted transgene integration via primed micro-homologues.Cell discovery · 2023Article
- Homology-Directed-Repair-Based Genome Editing in HSPCs for the Treatment of Inborn Errors of Immunity and Blood Disorders.Pharmaceutics · 2023Review
- Increased Gene Targeting in Hyper-Recombinogenic LymphoBlastoid Cell Lines Leaves Unchanged DSB Processing by Homologous Recombination.International journal of molecular sciences · 2022Article
- CRISPR-based genome editing through the lens of DNA repair.Molecular cell · 2022Review
- Optimization of AAV6 transduction enhances site-specific genome editing of primary human lymphocytes.Molecular therapy. Methods & clinical development · 2021Article
- Analyzing Plant Gene Targeting Outcomes and Conversion Tracts with Nanopore Sequencing.International journal of molecular sciences · 2021Article
- Efficient gene targeting in Nicotiana tabacum using CRISPR/SaCas9 and temperature tolerant LbCas12a.Plant biotechnology journal · 2021Article
- Bi-allelic MCM10 variants associated with immune dysfunction and cardiomyopathy cause telomere shortening.Nature communications · 2021Article
- RAD52: Viral Friend or Foe?Cancers · 2020Review
- Molecular characterization of precise in vivo targeted gene integration in human cells using AAVHSC15.PloS one · 2020Article
- Strategies for Efficient Genome Editing Using CRISPR-Cas9.Genetics · 2019Article
- Real-time observation of DNA target interrogation and product release by the RNA-guided endonuclease CRISPR Cpf1 (Cas12a).Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Simplified Footprint-Free Cas9/CRISPR Editing of Cardiac-Associated Genes in Human Pluripotent Stem Cells.Stem cells and development · 2018Article
- Precision genome editing using synthesis-dependent repair of Cas9-induced DNA breaks.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Modeling of Autism Using Organoid Technology.Molecular neurobiology · 2017Review
- Gene Editing with Helper-Dependent Adenovirus Can Efficiently Introduce Multiple Changes Simultaneously over a Large Genomic Region.Molecular therapy. Nucleic acids · 2017Article
- Targeted Genome Replacement via Homology-directed Repair in Non-dividing Cardiomyocytes.Scientific reports · 2017Article
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Authors and funding
4 authors.
Funding
Abstract
Gene targeting in human somatic cells is of importance because it can be used to either delineate the loss-of-function phenotype of a gene or correct a mutated gene back to wild-type. Both of these outcomes require a form of DNA double-strand break (DSB) repair known as homologous recombination (HR). The mechanism of HR leading to gene targeting, however, is not well understood in human cells. Here, we demonstrate that a two-end, ends-out HR intermediate is valid for human gene targeting. Furthermore, the resolution step of this intermediate occurs via the classic DSB repair model of HR while synthesis-dependent strand annealing and Holliday Junction dissolution are, at best, minor pathways. Moreover, and in contrast to other systems, the positions of Holliday Junction resolution are evenly distributed along the homology arms of the targeting vector. Most unexpectedly, we demonstrate that when a meganuclease is used to introduce a chromosomal DSB to augment gene targeting, the mechanism of gene targeting is inverted to an ends-in process. Finally, we demonstrate that the anti-recombination activity of mismatch repair is a significant impediment to gene targeting. These observations significantly advance our understanding of HR and gene targeting in human cells.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.