"The research initially started with the aim of finding out the mechanisms of dosage compensation," explains Prof. Dr. Janosch Hennig, Chair of Biochemistry IV at the University of Bayreuth. With dosage compensation, most organisms ensure that X-linked genes of both sexes are read out on the same scale. The fruit fly (Drosophila) was used as a model organism. "Here, dosage compensation proceeds differently than in humans, but the protein components involved are all present and conserved in humans."
The study by Prof. Dr. Janosch Hennig and his co-worker Dr. Pravin Jagtap is important because the DExH-type RNA helicase maleless (MLE) under investigation is similar to the DHX9 RNA helicase in humans. DHX9 has a great therapeutic potential, as it plays an important role in diseases such as cancer, HIV and other autoimmune diseases. "Using our structures, we have now been able to find a site on the surface of the enzyme for which highly specific inhibitors can be developed," says Hennig. "We are already working on this next step."
During the investigations, Hennig and his team discovered that an MLE adopts different conformations, i.e. a spatial arrangement of the atoms of a molecule, during RNA remodeling. These structures provide a detailed explanation of the unwinding process of RNA.
"There is a lot of research being done on these enzymes, but no one has been able to determine a structure of such a helicase when it is present in the double-stranded RNA bound state," Hennig says. "We have now been able to show that with this study. Furthermore, we were able to solve five additional structures using cryo-electron microscopy and could thus decipher almost the complete enzymatic mechanism." The importance of the structural data of the Bayreuth scientists Hennig and Jagtap was confirmed in cells in collaboration by the research group of Prof. Dr. Peter Becker of the Ludwig Maximilian University, Munich.
The research was funded by the German Research Foundation. Dr. Pravin Jagtap was also co-funded through the EU Marie Curie Actions Cofund EIPOD program.
