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Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy

Author

Listed:
  • Sven Bervoets

    (University of Antwerp)

  • Na Wei

    (The Scripps Research Institute)

  • Maria-Luise Erfurth

    (University of Antwerp)

  • Shazie Yusein-Myashkova

    (University of Antwerp
    Bulgarian Academy of Sciences)

  • Biljana Ermanoska

    (University of Antwerp
    Brandeis University)

  • Ligia Mateiu

    (University of Antwerp)

  • Bob Asselbergh

    (University of Antwerp)

  • David Blocquel

    (The Scripps Research Institute)

  • Priyanka Kakad

    (Florida Atlantic University)

  • Tyrone Penserga

    (Florida Atlantic University)

  • Florian P Thomas

    (Hackensack University Medical Center)

  • Velina Guergueltcheva

    (University Hospital Sofiamed, Sofia University St. Kliment Ohridski)

  • Ivailo Tournev

    (Medical University-Sofia
    New Bulgarian University)

  • Tanja Godenschwege

    (Florida Atlantic University)

  • Albena Jordanova

    (University of Antwerp
    Medical University-Sofia)

  • Xiang-Lei Yang

    (The Scripps Research Institute)

Abstract

Charcot-Marie-Tooth disease (CMT) is a length-dependent peripheral neuropathy. The aminoacyl-tRNA synthetases constitute the largest protein family implicated in CMT. Aminoacyl-tRNA synthetases are predominantly cytoplasmic, but are also present in the nucleus. Here we show that a nuclear function of tyrosyl-tRNA synthetase (TyrRS) is implicated in a Drosophila model of CMT. CMT-causing mutations in TyrRS induce unique conformational changes, which confer capacity for aberrant interactions with transcriptional regulators in the nucleus, leading to transcription factor E2F1 hyperactivation. Using neuronal tissues, we reveal a broad transcriptional regulation network associated with wild-type TyrRS expression, which is disturbed when a CMT-mutant is expressed. Pharmacological inhibition of TyrRS nuclear entry with embelin reduces, whereas genetic nuclear exclusion of mutant TyrRS prevents hallmark phenotypes of CMT in the Drosophila model. These data highlight that this translation factor may contribute to transcriptional regulation in neurons, and suggest a therapeutic strategy for CMT.

Suggested Citation

  • Sven Bervoets & Na Wei & Maria-Luise Erfurth & Shazie Yusein-Myashkova & Biljana Ermanoska & Ligia Mateiu & Bob Asselbergh & David Blocquel & Priyanka Kakad & Tyrone Penserga & Florian P Thomas & Veli, 2019. "Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12909-9
    DOI: 10.1038/s41467-019-12909-9
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    Cited by:

    1. Biljana Ermanoska & Bob Asselbergh & Laura Morant & Maria-Luise Petrovic-Erfurth & Seyyedmohsen Hosseinibarkooie & Ricardo Leitão-Gonçalves & Leonardo Almeida-Souza & Sven Bervoets & Litao Sun & LaTas, 2023. "Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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