Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers

Manaswini Sivaramakrishnan, Kathleen D. McCarthy, Sébastien Campagne, Sylwia Huber, Sonja Meier, Angélique Augustin, Tobias Heckel, Hélène Meistermann, Melanie N. Hug, Pascale Birrer, Ahmed Moursy, Sarah Khawaja, Roland Schmucki, Nikos Berntenis, Nicolas Giroud, Sabrina Golling, Manuel Tzouros, Balazs Banfai, Gonzalo Duran-Pacheco, Jens Lamerz, Ying Hsiu Liu, Thomas Luebbers, Hasane Ratni, Martin Ebeling (), Antoine Cléry, Sergey Paushkin, Adrian R. Krainer, Frédéric H.-T. Allain and Friedrich Metzger ()
Additional contact information
Manaswini Sivaramakrishnan: Roche Innovation Center Basel
Kathleen D. McCarthy: Roche Innovation Center Basel
Sébastien Campagne: ETH Zurich
Sylwia Huber: Roche Innovation Center Basel
Sonja Meier: Roche Innovation Center Basel
Angélique Augustin: Roche Innovation Center Basel
Tobias Heckel: Roche Innovation Center Basel
Hélène Meistermann: Roche Innovation Center Basel
Melanie N. Hug: Roche Innovation Center Basel
Pascale Birrer: Roche Innovation Center Basel
Ahmed Moursy: ETH Zurich
Sarah Khawaja: ETH Zurich
Roland Schmucki: Roche Innovation Center Basel
Nikos Berntenis: Roche Innovation Center Basel
Nicolas Giroud: Roche Innovation Center Basel
Sabrina Golling: Roche Innovation Center Basel
Manuel Tzouros: Roche Innovation Center Basel
Balazs Banfai: Roche Innovation Center Basel
Gonzalo Duran-Pacheco: Roche Innovation Center Basel
Jens Lamerz: Roche Innovation Center Basel
Ying Hsiu Liu: Cold Spring Harbor Laboratory
Thomas Luebbers: Roche Innovation Center Basel
Hasane Ratni: Roche Innovation Center Basel
Martin Ebeling: Roche Innovation Center Basel
Antoine Cléry: ETH Zurich
Sergey Paushkin: SMA Foundation
Adrian R. Krainer: Cold Spring Harbor Laboratory
Frédéric H.-T. Allain: ETH Zurich
Friedrich Metzger: Roche Innovation Center Basel

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes. In addition to the therapeutic potential of these molecules for treatment of SMA, our work has wide-ranging implications in understanding how small molecules can interact with specific quaternary RNA structures.

Date: 2017
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DOI: 10.1038/s41467-017-01559-4

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