RNA Targets and Function of Topoisomerase 3ß in Reducing Stress in Neuronal Physiology
Topoisomerase 3ß (Top3ß) relaxes DNA and RNA and its dysregulation is implicated in various neurodevelopmental and cognitive disorders. We developed a novel protocol to isolate RNA targets of the topoisomerase without artificial cross-linking and demonstrated that topoisomerase activity toward long RNAs is useful in cells where mRNAs travel over long distances and require strict translational control. We show that such mRNAs depend on the RNA topoisomerase activity for their proper expression and localization. Lack of the enzymatic activity of Top3ß stresses neurons, affecting the morphology of the neuromuscular junction (NMJ) in larvae and adult flies, aging, and the coordinated movement of older flies. The interaction network of Top3ß links it to all levels of posttranscriptional RNA expression, splicing, localization, translation, and RNA stability. This study provides insights into the mechanisms underlying neurological diseases, including schizophrenia, autism spectrum disorders, and Fragile X syndrome, diseases to which Top3ß and many of its interactors, particularly Tdrd3 and FMR1, have been linked.