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Scientific result | DNA | Gene and cell therapy
Certain mobile DNA sequences shape genomes and are maintained over the course of generations. How is this explained? The interaction between two proteins, which is essential for their integration into a specific area of the yeast genome, has been identified. This finding has interesting implications for gene therapy.
Transposable elements are DNA sequences that can move about in genomes. They are represented in a significant fraction of genomes and play an important role in their evolution. By integrating within the DNA, these elements can contribute to the plasticity of the genome and the emergence of new cellular functions. Conversely, they can also cause mutations that endanger the lives of cells. Their integration typically occurs in specific areas that are low in genes, where integration is less harmful. The mechanisms that allow this targeted integration are still not well understood.
In order to examine how the integration site is determined, researchers at the Pathology and Molecular Virology laboratory (CNRS/Inserm/Université Paris Diderot), in collaboration with researchers from the CEA-IBITECS and the University of Minnesota (USA), took an interest in the Ty1 retrotransposon1 from the yeast Saccharomyces cerevisiae. Ty1 integrates within a narrow region situated upstream of specific genes, all of which are transcribed by the enzyme complex RNA polymerase III (Pol III). Using Pol III as a bait, the researchers discovered that one of the proteins in this complex, AC40, interacts with the protein encoded by Ty1 to allow its integration. Further analyses have shown that this interaction is essential for the targeted integration of the transposable element. Apart from the advance in basic research, elucidating the Ty1 integration mechanism is also interesting for gene therapy. The latter uses vectors derived from retroviruses in order to transfer genes into cells. Like retroviruses, these vectors are often integrated in gene-rich regions, where they can have mutagenic effects. The properties of transposable elements such as Ty1 could be used to limit the effects of gene transfer vectors, by controlling their integration into lower-risk regions.
An RNA polymerase III subunit determines sites of retrotransposon integration | Science
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.