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

Abstract

Topoisomerases are crucial to solve DNA topological problems, but they have not been linked to RNA metabolism. Here we show that human topoisomerase 3β (Top3β) is an RNA topoisomerase that biochemically and genetically interacts with FMRP, a protein deficient in Fragile X syndrome and known to regulate translation of mRNAs important for neuronal function and autism. Notably, the FMRP-Top3β interaction is abolished by a disease-associated FMRP mutation, suggesting that Top3β may contribute to pathogenesis of mental disorders. Top3β binds multiple mRNAs encoded by genes with neuronal functions related to schizophrenia and autism. Expression of one such gene, ptk2/FAK, is reduced in neuromuscular junctions of Top3β mutant flies. Synapse formation is defective in Top3β mutant flies and mice, as observed in FMRP mutant animals. Our findings suggest that Top3β acts as an RNA topoisomerase and works with FMRP to promote expression of mRNAs critical for neurodevelopment and mental health.

Proteolytic Degradation of Topoisomerase II (Top2) Enables the Processing of Top2·DNA and Top2·RNA Covalent Complexes by Tyrosyl-DNA-Phosphodiesterase 2 (TDP2)

“…In closing, it is relevant to note that in type IA topoisomerases, the Top3 enzymes also form 5Ј-tyrosyl catalytic intermediates (2,42). Thus, further studies are warranted to determine the potential relevance of TDP2 for the repair of Top3␣⅐DNA and Top3␤⅐DNA or RNA complexes (42)(43)(44)(45).…”

DNA and RNA topoisomerase activities of Top3β are promoted by mediator protein Tudor domain-containing protein 3

“…The interest is further boosted by recent experiments demonstrating that human and Drosophila topoisomerase 3β (Top3β) is associated with mRNA in cytoplasm and has RNA topoisomerase activity (11,12). The deficiency in this enzyme is attributed to one of the causative mutations for schizophrenia and cognitive disorder (11, 12) and results in abnormal synaptic structures in Drosophila (12).…”

“…FMRP is preferentially localized in the coding regions of mRNA and plays a role in inhibiting the translation of mRNA relevant to synaptic functions in neuronal cells (17). It is thus suggested that Top3β may also have a role in translation through its RNA topoisomerase activity in modulating the complex structures of folded mRNA (12). Whereas Top3β can have important functions in two processes of gene expression in nucleus and cytoplasm through its interactions with TDRD3, it is unclear whether TDRD3 has any additional role in regulating Top3β activity, beyond its targeting function of directing Top3β to critical sites in subcellular compartments.…”

Topoisomerase 1 inhibition reversibly impairs synaptic function

“…For instance, topoisomerase 1 (TOP1) and topoisomerase 2 (TOP2) inhibitors transcriptionally up-regulate the paternal copy of Ubiquitin-protein ligase E3A (Ube3a) (5), a gene that affects synaptic activity and that is deleted or duplicated in distinct neurodevelopmental disorders (Angelman syndrome and autism, respectively) (6,7). Moreover, a de novo mutation in Top1 and de novo mutations in genes that interact with Top1 and Top3b were identified recently in patients with autism (8,9), whereas deletion of Top3b increases the risk for schizophrenia and intellectual disability (10,11). Top2b is also required for axon outgrowth in different regions of the nervous system and for the survival of postmitotic neurons (12)(13)(14)(15).…”