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

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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.

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Most cited references 47

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De novo gene disruptions in children on the autistic spectrum.

Ivan Iossifov, Michael Ronemus, Dan Levy … (2012)

Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

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HITS-CLIP yields genome-wide insights into brain alternative RNA processing

Donny D. Licatalosi, Aldo Mele, John Fak … (2008)

Summary Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3′ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

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Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.

A. Verkerk, M Pieretti, J Sutcliffe … (1991)

Fragile X syndrome is the most frequent form of inherited mental retardation and is associated with a fragile site at Xq27.3. We identified human YAC clones that span fragile X site-induced translocation breakpoints coincident with the fragile X site. A gene (FMR-1) was identified within a four cosmid contig of YAC DNA that expresses a 4.8 kb message in human brain. Within a 7.4 kb EcoRI genomic fragment, containing FMR-1 exonic sequences distal to a CpG island previously shown to be hypermethylated in fragile X patients, is a fragile X site-induced breakpoint cluster region that exhibits length variation in fragile X chromosomes. This fragment contains a lengthy CGG repeat that is 250 bp distal of the CpG island and maps within a FMR-1 exon. Localization of the brain-expressed FMR-1 gene to this EcoRI fragment suggests the involvement of this gene in the phenotypic expression of the fragile X syndrome.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9809671

Journal ID (pubmed-jr-id): 21092

Journal ID (nlm-ta): Nat Neurosci

Journal ID (iso-abbrev): Nat. Neurosci.

Title: Nature neuroscience

ISSN (Print): 1097-6256

ISSN (Electronic): 1546-1726

Publication date Nihms-submitted: 29 October 2013

Publication date (Electronic): 04 August 2013

Publication date (Print): September 2013

Publication date PMC-release: 01 March 2014

Volume: 16

Issue: 9

Electronic Location Identifier: 10.1038/nn.3479

Affiliations

[1 ]Genome Instability and Chromatin-Remodeling Section, Laboratory of Genetics

[2 ]State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China

[3 ]Human Genetics Section, Laboratory of Genetics

[4 ]Department of Biochemistry, University of Toronto, Toronto, Ont., Canada M5S 1A8

[5 ]Developmental Genomics and Aging Section, Laboratory of Genetics

[6 ]RNA Regulation Section, Laboratory of Genetics

[7 ]Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287

[8 ]Section of Infectious Diseases, Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520

[9 ]Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224

Author notes

[* ]Correspondence should be addressed to SZ and WW. Dr. Sige Zou, Telephone: 410-558-8461, Fax: 410-558-8302, zous@ 123456mail.nih.gov ; Dr. Weidong Wang, Telephone: 410-558-8334, Fax: 410-558-8331, wangw@ 123456grc.nia.nih.gov

[#]

co-first authors.

Article

Manuscript ID: NIHMS500267

DOI: 10.1038/nn.3479

PMC ID: 3853347

PubMed ID: 23912945

SO-VID: 5a964c02-6e42-4310-82be-e83bd0da06e4

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History

Funding

Funded by: National Institute on Aging : NIA

Award ID: Z01 AG000657-08 || AG

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