ArticleProceedings of the National Academy of Sciences of the United States of America2008
Ku70, an essential gene, modulates the frequency of rAAV-mediated gene targeting in human somatic cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 85 citations in OpenAlex.
- Ku limits aberrant mRNA splicing promoted by intronic antisense Alu elements.bioRxiv : the preprint server for biology · 2025Article
- AAV-mediated genome editing is influenced by the formation of R-loops.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Compared to other NHEJ factors, DNA-PK protein and RNA levels are markedly increased in all higher primates, but not in prosimians or other mammals.DNA repair · 2024Article
- AAV-mediated genome editing is influenced by the formation of R-loops.bioRxiv : the preprint server for biology · 2024Article
- Ablating putative Ku70 phosphorylation sites results in defective DNA damage repair and spontaneous induction of hepatocellular carcinoma.Nucleic acids research · 2021Article
- Review
- The Ku complex: recent advances and emerging roles outside of non-homologous end-joining.Cellular and molecular life sciences : CMLS · 2021Review
- Evaluating the Genomic Parameters Governing rAAV-Mediated Homologous Recombination.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Improved Genome Editing through Inhibition of FANCM and Members of the BTR Dissolvase Complex.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Enhancing CRISPR deletion via pharmacological delay of DNA-PKcs.Genome research · 2021Article
- Variation amongMicroorganisms · 2021Article
- Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells.Frontiers in cell and developmental biology · 2021Article
- Suppression of non-homologous end joining does not rescue DNA repair defects in Fanconi anemia patient cells.Cell cycle (Georgetown, Tex.) · 2020Article
- Human DNA-PK activates a STING-independent DNA sensing pathway.Science immunology · 2020Article
- Absence of XRCC4 and its paralogs in human cells reveal differences in outcomes for DNA repair and V(D)J recombination.DNA repair · 2020Article
- Advances in genome editing through control of DNA repair pathways.Nature cell biology · 2019Review
- PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ.Oncotarget · 2018Article
- PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF.Molecular cancer research : MCR · 2018Article
- Review
- Human somatic cells deficient for RAD52 are impaired for viral integration and compromised for most aspects of homology-directed repair.DNA repair · 2017Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Gene targeting has two important applications. One is the inactivation of genes ("knockouts"), and the second is the correction of a mutated allele back to wild-type ("gene therapy"). Central to these processes is the efficient introduction of the targeting DNA into the cells of interest. In humans, this targeting is often accomplished through the use of recombinant adeno-associated virus (rAAV). rAAV is presumed to use a pathway of DNA double-strand break (DSB) repair termed homologous recombination (HR) to mediate correct targeting; however, the specifics of this mechanism remain unknown. In this work, we attempted to generate Ku70-null human somatic cells by using a rAAV-based gene knockout strategy. Ku70 is the heterodimeric partner of Ku86, and together they constitute an end-binding activity that is required for a pathway [nonhomologous end joining (NHEJ)] of DSB repair that is believed to compete with HR. Our data demonstrated that Ku70 is an essential gene in human somatic cells. More importantly, however, in Ku70(+/-) cells, the frequency of gene targeting was 5- to 10-fold higher than in wild-type cells. RNA interference and short-hairpinned RNA strategies to deplete Ku70 phenocopied these results in wild-type cells and greatly accentuated them in Ku70(+/-) cell lines. Thus, Ku70 protein levels significantly influenced the frequency of rAAV-mediated gene targeting in human somatic cells. Our data suggest that gene-targeting frequencies can be significantly improved in human cells by impairing the NHEJ pathway, and we propose that Ku70 depletion can be used to facilitate both knockout and gene therapy approaches.
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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.