title: Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation.
abstract: Topoisomerases are crucial for solving 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 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-Top3β interaction is abolished by a disease-associated mutation of FMRP, suggesting that Top3β may contribute to the pathogenesis of mental disorders. Top3β 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 Top3β mutant flies. Synapse formation is defective in Top3β mutant flies and mice, as well as in FMRP mutant flies and mice. Our findings suggest that Top3β acts as an RNA topoisomerase and works with FMRP to promote the expression of mRNAs that are crucial for neurodevelopment and mental health.
authors.affiliation: Genome Instability and Chromatin-Remodeling Section, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Dongyi
authors.initials: D
authors.lastname: Xu
authors.forename: Weiping
authors.initials: W
authors.lastname: Shen
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.forename: Yutong
authors.initials: Y
authors.lastname: Xue
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Jian
authors.initials: J
authors.lastname: Sima
authors.forename: Jay
authors.initials: J
authors.lastname: Yang
authors.forename: Alexei
authors.initials: A
authors.lastname: Sharov
authors.forename: Subramanya
authors.initials: S
authors.lastname: Srikantan
authors.forename: Jiandong
authors.initials: J
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Fox
authors.forename: Yong
authors.initials: Y
authors.lastname: Qian
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martindale
authors.forename: Yulan
authors.initials: Y
authors.lastname: Piao
authors.forename: James
authors.initials: J
authors.lastname: Machamer
authors.forename: Samit R
authors.initials: SR
authors.lastname: Joshi
authors.forename: Subhasis
authors.initials: S
authors.lastname: Mohanty
authors.forename: Albert C
authors.initials: AC
authors.lastname: Shaw
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Lloyd
authors.forename: Grant W
authors.initials: GW
authors.lastname: Brown
authors.forename: Minoru S H
authors.initials: MS
authors.lastname: Ko
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.forename: Sige
authors.initials: S
authors.lastname: Zou
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D002645:Chickens; D004264:DNA Topoisomerases, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D004622:Embryo, Mammalian; D005123:Eye / Q000166:cytology / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009469:Neuromuscular Junction / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D016601:RNA-Binding Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D004264:DNA Topoisomerases, Type I; D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins
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