Gene hopping and cancer gene therapies

The way in which genes ‘jump’ to safe regions of the genome could improve gene therapy against cancer and other diseases.

An international team led by researchers from the Higher Council for Scientific Research (CSIC) in Spain and the National Center for Scientific Research (CNRS) in France has identified the mechanism that allows a group of transposons, also called jumping genes, to insert themselves into safe regions. of the genome, a process that facilitates adaptation to new external conditions without causing harmful genetic mutations. The results of the study open the way to improve gene therapies against cancer, in addition to those directed against other diseases such as haemophilia and certain congenital blindness.

Transposons or jumping genes are DNA sequences that only carry genetic information to be able to move within the genomes of living beings, a process that can lead to the appearance of mutations and changes in the amount of DNA in the genome. “The movement of transposons within the genome allows living beings to develop new cellular functions and, therefore, adapt to different environments, but it can pose a threat when this process generates harmful genetic mutations,” explains Sonia Huecas, a researcher at the Center for Margarita Salas Biological Research (CIB) of the CSIC and one of the main authors of the study. And she adds: “In fact, more than a hundred hereditary diseases have been attributed to new insertions of transposons.”

In the new study, the researchers have observed atomic-level details of the interaction between a protein, which catalyzes insertions of the most abundant transposon in Saccharomyces cerevisiae, baker’s yeast (a model organism), and an enzyme complex that binds to DNA to synthesize RNA: RNA polymerase III.

“Using cryoelectron microscopy, we have described how an unfolded region of the transposon-inserting protein engages in a crack on the surface of RNA polymerase III. In addition to serving as an anchor point for the protein, this interaction reconfigures RNA polymerase III so that it remains trapped on DNA for longer, thus increasing the chances of inserting the transposon into safe places in the yeast genome, a surprising finding.” comments Carlos Fernández Tornero, from the CIB, who has co-directed the study together with Pascale Lesage, from the Saint Louis Research Institute (IRSL) in France.

Model for insertion of the Ty1 retrotransposon into DNA. (Image: CIB / CSIC)

Improve vectors used in gene therapy

In addition to constituting an advance for basic research, this study could help to improve viral vectors, the transport medium that allows the genetic material of interest to be introduced into the patient, and on which gene therapies are currently based. They use vectors that are integrated into gene-rich regions of the genome, something that can have deleterious effects due to the possibility of harmful genetic mutations.

“The information obtained during our research with the yeast genome could be used to direct gene therapy vectors towards safe regions of the genome and thus limit their mutagenic potential”, highlights the CSIC researcher.

The study is titled “Structural basis of Ty1 integrase tethering to RNA polymerase III for targeted retrotransposon integration”. And it has been published in the academic journal Nature Communications. (Source: CIB / CSIC)