Despite the enormous potential of using transgenesis for gene function analysis and gene therapy, little is known about mechanisms of gene integration in eukyotic cells. Transgene integration into the chromomsomes of living cells can occur either randomly or targeted by homologous recombination. The later type of integration is the most useful, because it allows precisely deleting or modifying sequences at defined chromosomal positions. A consortium is formed to study gene integration by recombination in a number of different model organisms.
As DNA repair is conserved during evolution, a comparative genomics approach is proposed to discover evolutionary conserved principles of gene integration. An explicit goal is to understand why targeted integration occurs efficiently in some eukaryotic cells, but not in others. One explanation to be investigated is that the ratios of targeted to random integration reflects to the balance between DNA double-strand break repair byhomologous recombination and end-joining. Other areas of research will relate to site-specific integration by AdenoAssociatedViruses, T-elements, serine recombinases. The insight into mechanisms of gene integration will be used to increase the efficiency of targeted gene integration in cells, where targeted integration events are currently hard to detect. This might be achieved either by modification of the gene constructs, their transfer into the cell nucleus or by regulating the expression of transacting recombination factors. As gene targeting is theonly way to precisely modify the genetic blueprint of living cells in vivo, improvements of this technique offer immense opportunities not only for basic research, but also for biotechnology and gene therapy. This ranges from fine-tuning protein production in plants and bioreactors to gene therapy for autosomal dominant defects. Two companies are included in the proposal to capture these opportunities and reenforce the com.
Fields of science
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Funding SchemeSTREP - Specific Targeted Research Project