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The solution structure of Dead End bound to AU-rich RNA reveals an unusual mode of tandem RRM-RNA recognition required for mRNA regulation

Author

Listed:
  • Malgorzata M. Duszczyk

    (Institute of Molecular Biology and Biophysics, ETH Zürich)

  • Harry Wischnewski

    (Institute of Molecular Health Sciences, ETH Zürich)

  • Tamara Kazeeva

    (Institute of Molecular Biology and Biophysics, ETH Zürich)

  • Rajika Arora

    (Institute of Molecular Health Sciences, ETH Zürich)

  • Fionna E. Loughlin

    (Institute of Molecular Biology and Biophysics, ETH Zürich
    Monash University)

  • Christine Schroetter

    (Institute of Molecular Biology and Biophysics, ETH Zürich
    Institute of Biochemistry, Department of Biology, ETH Zürich)

  • Ugo Pradère

    (Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich)

  • Jonathan Hall

    (Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich)

  • Constance Ciaudo

    (Institute of Molecular Health Sciences, ETH Zürich)

  • Frédéric H.-T. Allain

    (Institute of Molecular Biology and Biophysics, ETH Zürich
    Institute of Biochemistry, Department of Biology, ETH Zürich)

Abstract

Dead End (DND1) is an RNA-binding protein essential for germline development through its role in post-transcriptional gene regulation. The molecular mechanisms behind selection and regulation of its targets are unknown. Here, we present the solution structure of DND1’s tandem RNA Recognition Motifs (RRMs) bound to AU-rich RNA. The structure reveals how an NYAYUNN element is specifically recognized, reconciling seemingly contradictory sequence motifs discovered in recent genome-wide studies. RRM1 acts as a main binding platform, including atypical extensions to the canonical RRM fold. RRM2 acts cooperatively with RRM1, capping the RNA using an unusual binding pocket, leading to an unusual mode of tandem RRM-RNA recognition. We show that the consensus motif is sufficient to mediate upregulation of a reporter gene in human cells and that this process depends not only on RNA binding by the RRMs, but also on DND1’s double-stranded RNA binding domain (dsRBD), which is dispensable for binding of a subset of targets in cellulo. Our results point to a model where DND1 target selection is mediated by a non-canonical mode of AU-rich RNA recognition by the tandem RRMs and a role for the dsRBD in the recruitment of effector complexes responsible for target regulation.

Suggested Citation

  • Malgorzata M. Duszczyk & Harry Wischnewski & Tamara Kazeeva & Rajika Arora & Fionna E. Loughlin & Christine Schroetter & Ugo Pradère & Jonathan Hall & Constance Ciaudo & Frédéric H.-T. Allain, 2022. "The solution structure of Dead End bound to AU-rich RNA reveals an unusual mode of tandem RRM-RNA recognition required for mRNA regulation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33552-x
    DOI: 10.1038/s41467-022-33552-x
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    References listed on IDEAS

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    1. Noriko Handa & Osamu Nureki & Kazuki Kurimoto & Insil Kim & Hiroshi Sakamoto & Yoshiro Shimura & Yutaka Muto & Shigeyuki Yokoyama, 1999. "Structural basis for recognition of the tra mRNA precursor by the Sex-lethal protein," Nature, Nature, vol. 398(6728), pages 579-585, April.
    2. Fruzsina Hobor & Andre Dallmann & Neil J. Ball & Carla Cicchini & Cecilia Battistelli & Roksana W. Ogrodowicz & Evangelos Christodoulou & Stephen R. Martin & Alfredo Castello & Marco Tripodi & Ian A. , 2018. "A cryptic RNA-binding domain mediates Syncrip recognition and exosomal partitioning of miRNA targets," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    3. Kirsten K. Youngren & Douglas Coveney & Xiaoning Peng & Chitralekha Bhattacharya & Laura S. Schmidt & Michael L. Nickerson & Bruce T. Lamb & Jian Min Deng & Richard R. Behringer & Blanche Capel & Edwa, 2005. "The Ter mutation in the dead end gene causes germ cell loss and testicular germ cell tumours," Nature, Nature, vol. 435(7040), pages 360-364, May.
    4. Masashi Yamaji & Miki Jishage & Cindy Meyer & Hemant Suryawanshi & Evan Der & Misaki Yamaji & Aitor Garzia & Pavel Morozov & Sudhir Manickavel & Hannah L. McFarland & Robert G. Roeder & Markus Hafner , 2017. "DND1 maintains germline stem cells via recruitment of the CCR4–NOT complex to target mRNAs," Nature, Nature, vol. 543(7646), pages 568-572, March.
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