Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7

  1. Irene Beusch
  2. Pierre Barraud  Is a corresponding author
  3. Ahmed Moursy
  4. Antoine Cléry
  5. Frédéric Hai-Trieu Allain  Is a corresponding author
  1. Institute of Molecular Biology and Biophysics, ETH Zurich, Switzerland

Abstract

HnRNP A1 regulates many alternative splicing events by the recognition of splicing silencer elements. Here, we provide the solution structures of its two RNA recognition motifs (RRMs) in complex with short RNA. In addition, we show by NMR that both RRMs of hnRNP A1 can bind simultaneously to a single bipartite motif of the human intronic splicing silencer ISS-N1, which controls survival of motor neuron exon 7 splicing. RRM2 binds to the upstream motif and RRM1 to the downstream motif. Combining the insights from the structure with in cell splicing assays we show that the architecture and organization of the two RRMs is essential to hnRNP A1 function. The disruption of the inter-RRM interaction or the loss of RNA binding capacity of either RRM impairs splicing repression by hnRNP A1. Furthermore, both binding sites within the ISS-N1 are important for splicing repression and their contributions are cumulative rather than synergistic.

Article and author information

Author details

  1. Irene Beusch

    Institute of Molecular Biology and Biophysics, ETH Zurich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Pierre Barraud

    Institute of Molecular Biology and Biophysics, ETH Zurich, Zürich, Switzerland
    For correspondence
    pierre.barraud@cnrs.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4460-8360
  3. Ahmed Moursy

    Institute of Molecular Biology and Biophysics, ETH Zurich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Antoine Cléry

    Institute of Molecular Biology and Biophysics, ETH Zurich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Frédéric Hai-Trieu Allain

    Institute of Molecular Biology and Biophysics, ETH Zurich, Zürich, Switzerland
    For correspondence
    allain@mol.biol.ethz.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2131-6237

Funding

ETH Zurich

  • Frédéric Hai-Trieu Allain

Centre National de la Recherche Scientifique

  • Pierre Barraud

Swiss National Science Foundation NCCR Structural Biology

  • Frédéric Hai-Trieu Allain

Swiss National Science Foundation NCCR RNA and Disease

  • Frédéric Hai-Trieu Allain

SMA Europe

  • Frédéric Hai-Trieu Allain

ETH Fellowship Program (Post-doc fellowship)

  • Pierre Barraud

Novartis Foundation (Post-doc fellowship)

  • Pierre Barraud

Cure SMA

  • Antoine Cléry
  • Frédéric Hai-Trieu Allain

Fondation Suisse de Recherche sur les Maladies Musculaires

  • Antoine Cléry
  • Frédéric Hai-Trieu Allain

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Juan Valcárcel, Centre de Regulació Genòmica (CRG), Barcelona, Spain

Publication history

  1. Received: February 3, 2017
  2. Accepted: June 23, 2017
  3. Accepted Manuscript published: June 26, 2017 (version 1)
  4. Version of Record published: July 10, 2017 (version 2)

Copyright

© 2017, Beusch et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Irene Beusch
  2. Pierre Barraud
  3. Ahmed Moursy
  4. Antoine Cléry
  5. Frédéric Hai-Trieu Allain
(2017)
Tandem hnRNP A1 RNA recognition motifs act in concert to repress the splicing of survival motor neuron exon 7
eLife 6:e25736.
https://doi.org/10.7554/eLife.25736

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