Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation

Topoisomerases are crucial for solving DNA topological problems, but they have not been linked to RNA metabolism. Here we show that human topoisomerase 3 beta (Top3 beta) is an RNA topoisomerase that biochemically and genetically interacts with FMRP, a protein that is deficient in fragile X syndrome and is known to regulate the translation of mRNAs that are important for neuronal function, abnormalities of which are linked to autism. Notably, the FMRP-Top3 beta interaction is abolished by a disease-associated mutation of FMRP, suggesting that Top3 beta may contribute to the pathogenesis of mental disorders. Top3 beta binds multiple mRNAs encoded by genes with neuronal functions linked to schizophrenia and autism. Expression of one such gene, that encoding protein tyrosine kinase 2 (ptk2, also known as focal adhesion kinase or FAK), is reduced in the neuromuscular junctions of Top3 beta mutant flies. Synapse formation is defective in Top3 beta mutant flies and mice, as well as in FMRP mutant flies and mice. Our findings suggest that Top3 beta acts as an RNA topoisomerase and works with FMRP to promote the expression of mRNAs that are crucial for neurodevelopment and mental health.