Analysis of the integrant in MyK-103 transgenic mice in which males fail to transmit the integrant.

Wilkie, Thomas M.; Palmiter, Richard D.

doi:10.1128/mcb.7.5.1646

Cited by 96 publications

(76 citation statements)

References 65 publications

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“…Such findings are a recurrent theme: many other investigators have found Topo I consensus sequences, and other sequences such as Escherichia coli CHI element and minisatellite sequences, near transgene-chromosome junctions. 43,44,59,94,95 It has been demonstrated that integration of a circular bent DNA-containing vector preferentially occurs at the bent site, while bent DNA structures are often found at illegitimate recombination junctions and rearrangement breakpoints. 76 This suggests that such bent DNA sites in the genome (which are numerous) might be involved in integration.…”

Section: Illegitimate Integration Sites Are Not Totally Randommentioning

confidence: 99%

“…44 However, more complex insertion patterns are frequently observed (see Figure 2b). The recipient genomic locus can undergo extensive physical rearrangements at the site of integration, 45,50,51,58,59 including deletions (as much as tens of kb), duplications, and translocations, among others. 43,52,60 Another consequence is that the integrated material can interrupt coding sequences.…”

Section: Introductionmentioning

confidence: 99%

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Illegitimate DNA integration in mammalian cells

2003

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Foreign DNA integration is one of the most widely exploited cellular processes in molecular biology. Its technical use permits us to alter a cellular genome by incorporating a fragment of foreign DNA into the chromosomal DNA. This process employs the cell's own endogenous DNA modification and repair machinery. Two main classes of integration mechanisms exist: those that draw on sequence similarity between the foreign and genomic sequences to carry out homology-directed modifications, and the nonhomologous or 'illegitimate' insertion of foreign DNA into the genome. Gene therapy procedures can result in illegitimate integration of introduced sequences and thus pose a risk of unforeseeable genomic alterations. The choice of insertion site, the degree to which the foreign DNA and endogenous locus are modified before or during integration, and the resulting impact on structure, expression, and stability of the genome are all factors of illegitimate DNA integration that must be considered, in particular when designing genetic therapies.

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Section: Illegitimate Integration Sites Are Not Totally Randommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Illegitimate DNA integration in mammalian cells

2003

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“…A duplication of the target is possible when the T-DNA integrates at a staggered nick or when integration occurs at breakpoints between sister chromatids within a replication bubble (see Fig. 5C), as postulated by Wilkie and Palmiter (1987). T-DNAs arranged in tandem or inverted repeats could be the consequence of end ligation of T-DNA copies before insertion, but the inverted repeats are more likely due to strand switching during repair at the T-DNA ends (Jorgensen et al 1987).…”

Section: Variations On the Modelmentioning

confidence: 99%

Illegitimate recombination in plants: a model for T-DNA integration.

Gheysen¹,

Villarroel²,

Montagu³

1991

Genes Dev.

266

201

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Agrobacterium tumefaciens is a soil bacterium capable of transferring DNA (the T-DNA) to the genome of higher plants, where it is then stably integrated. Six T-DNA inserts and their corresponding preinsertion sites were cloned from Arabidopsis thaliana and analyzed. Two T-DNA integration events from Nicotiana tabacum were included in the analysis. Nucleotide sequence comparison of plant target sites before and after T-DNA integration showed that the T-DNA usually causes only a small (13-28 bp) deletion in the plant DNA, but larger target rearrangements can occur. Short homologies between the T-DNA ends and the target sites, as well as the presence of filler sequences at the junctions, indicate that T-DNA integration is mediated by illegitimate recombination and that these processes in plants are very analogous to events in mammalian cells. We propose a model for T-DNA integration on the basis of limited base-pairing for initial synapsis, followed by DNA repair at the junctions. Variations of the model can explain the formation of filler DNA at the junctions by polymerase slipping and template switching during DNA repair synthesis and the presence of larger plant target DNA rearrangements.

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“…This suggests that integration occurs during DNA replication. Wilkie and Palmiter [48] have proposed that the free ends of the transgene initiate recombination by invading a replication "eye".…”

Section: Illegitimate Recombinationmentioning

confidence: 99%

Theoretical mechanisms in targeted and random integration of transgene DNA

Smith

2001

Reprod. Nutr. Dev.

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Analysis of the integrant in MyK-103 transgenic mice in which males fail to transmit the integrant.

Cited by 96 publications

References 65 publications

Illegitimate DNA integration in mammalian cells

Illegitimate DNA integration in mammalian cells

Illegitimate recombination in plants: a model for T-DNA integration.

Theoretical mechanisms in targeted and random integration of transgene DNA

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