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.

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Acknowledgements

We thank T. Hsieh (Duke University) for Drosophila Top3β reagents; J.C. Wang (Harvard University) for Top3β knockout mice; D. Zarnescu (University of Illinois), T. Jongens (University of Pennsylvania) and G. Dreyfuss (University of Pennsylvania) for dfmr1 fly strains and antibodies; S. Warren (Emory University), S. Ceman (University of Illinois) and Y. Feng (Emory University) for vectors of FMR1 variants; U. Fischer (University of Wuerzburg) for vectors of TDRD3 and FMR1 orthologs; A. Hoogeveen (Erasmus University) for FXR1 and FXR2 antibodies; R. Hynes (Massachusetts Institute of Technology) and R. Palmer (Umea University) for FAK reagents; T. Enomoto (Tohoku University) for Top3b−/− DT40 cells; and R. Hanai (Rikkyo University) for the Top3β vector. We thank E. Chen, D.J. Pan and Y. Feng for advice and assistance, S.K. Lee for assistance and D. Schlessinger for support and critical reading of the manuscript. This work is supported in part by the Intramural Research Program of the NIA (Z01 AG000657-08), the NIH, the Johns Hopkins Center for Neuroscience Research (NS050274), Canadian Institutes of Health research grant MOP-79368 (to G.W.B.), the National Basic Research Program of China (2013CB911002) and the National Natural Science Foundation of China (31271435). This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, Maryland, USA (http://biowulf.nih.gov).

Author information

Author notes

    • Dongyi Xu
    •  & Weiping Shen

    These authors contributed equally to this work.

Affiliations

  1. Genome Instability and Chromatin-Remodeling Section, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, Maryland, USA.

    • Dongyi Xu
    • , Weiping Shen
    • , Rong Guo
    • , Yutong Xue
    • , Wei Peng
    • , Jiandong Yang
    • , David Fox III
    •  & Weidong Wang
  2. State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.

    • Dongyi Xu
  3. Human Genetics Section, NIA, NIH, Baltimore, Maryland, USA.

    • Jian Sima
  4. Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

    • Jay Yang
    •  & Grant W Brown
  5. Developmental Genomics and Aging Section, NIA, NIH, Baltimore, Maryland, USA.

    • Alexei Sharov
    • , Yong Qian
    • , Yulan Piao
    •  & Minoru S H Ko
  6. RNA Regulation Section, Laboratory of Genetics, NIA, NIH, Baltimore, Maryland, USA.

    • Subramanya Srikantan
    • , Jennifer L Martindale
    •  & Myriam Gorospe
  7. Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • James Machamer
    •  & Thomas E Lloyd
  8. Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Samit R Joshi
    • , Subhasis Mohanty
    •  & Albert C Shaw
  9. Translational Gerontology Branch, NIA, NIH, Baltimore, Maryland, USA.

    • Sige Zou

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Contributions

D.X., W.S., R.G., Y.X., W.P., J.S., Jay Yang, S.S., Jiandong Yang, D.F., J.L.M., Y.P., J.M., S.R.J. and S.M. conducted experiments. A.C.S., T.E.L., G.W.B., M.S.H.K., M.G., S.Z. and W.W. supervised the project. A.S., Y.Q., D.X., W.S., R.G., Y.X., W.P., J.S., Jay Yang, S.S., A.C.S., T.E.L., G.W.B., M.S.H.K., M.G., S.Z. and W.W. analyzed the data. D.X., W.S., M.G., S.Z. and W.W. wrote the manuscript with input from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sige Zou or Weidong Wang.

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https://doi.org/10.1038/nn.3479

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