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

View ORCID ProfileMalgorzata M. Duszczyk, Harry Wischnewski, Tamara Kazeeva, View ORCID ProfileFionna E. Loughlin, Christine von Schroetter, Ugo Pradère, Jonathan Hall, View ORCID ProfileConstance Ciaudo, Frédéric H.-T. Allain
doi: https://doi.org/10.1101/572156
Malgorzata M. Duszczyk
1Institute of Molecular Biology and Biophysics, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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  • ORCID record for Malgorzata M. Duszczyk
  • For correspondence: malgosia@mol.biol.ethz.ch cciaudo@ethz.ch allain@mol.biol.ethz.ch
Harry Wischnewski
2Institute of Molecular Health Sciences, Department of Biology, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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Tamara Kazeeva
1Institute of Molecular Biology and Biophysics, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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Fionna E. Loughlin
1Institute of Molecular Biology and Biophysics, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
4Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800 VIC, Australia
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Christine von Schroetter
1Institute of Molecular Biology and Biophysics, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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Ugo Pradère
3Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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Jonathan Hall
3Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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Constance Ciaudo
2Institute of Molecular Health Sciences, Department of Biology, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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  • For correspondence: malgosia@mol.biol.ethz.ch cciaudo@ethz.ch allain@mol.biol.ethz.ch
Frédéric H.-T. Allain
1Institute of Molecular Biology and Biophysics, Department of Chemistry and Applied Biosciences, ETH Zürich, 8093, Zürich, Switzerland
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  • For correspondence: malgosia@mol.biol.ethz.ch cciaudo@ethz.ch allain@mol.biol.ethz.ch
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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 unusual extensions to the canonical RRM fold. RRM2 acts cooperatively with RRM1, capping the RNA using an unusual binding pocket, leading to an unprecedented 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), that we show to be dispensable for target binding in cellulo. Our results point to a model where DND1 target selection is mediated by an uncanonical 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.

Author comment A previous version of this manuscript contained an error in the normalization of the luciferase activity in the cell-based assays in Figures 5 and S8. This has been corrected and the text has been updated accordingly.

Footnotes

  • ↵5 Lead Contact

  • A previous version of this manuscript contained an error in the normalization of the luciferase activity in the cell-based assays in Figures 5 and S8. This has been corrected and the text has been updated accordingly.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 10, 2019.
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The solution structure of Dead End bound to AU-rich RNA reveals an unprecedented mode of tandem RRM-RNA recognition required for mRNA regulation
Malgorzata M. Duszczyk, Harry Wischnewski, Tamara Kazeeva, Fionna E. Loughlin, Christine von Schroetter, Ugo Pradère, Jonathan Hall, Constance Ciaudo, Frédéric H.-T. Allain
bioRxiv 572156; doi: https://doi.org/10.1101/572156
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The solution structure of Dead End bound to AU-rich RNA reveals an unprecedented mode of tandem RRM-RNA recognition required for mRNA regulation
Malgorzata M. Duszczyk, Harry Wischnewski, Tamara Kazeeva, Fionna E. Loughlin, Christine von Schroetter, Ugo Pradère, Jonathan Hall, Constance Ciaudo, Frédéric H.-T. Allain
bioRxiv 572156; doi: https://doi.org/10.1101/572156

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