Binding to SMN2 Pre-mRNA-protein Complex Elicits Specificity for Small Molecule Splicing Modifiers

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Nov 15

PMID 29133793

Citations 107

Authors

Manaswini Sivaramakrishnan

Kathleen D McCarthy

Sebastien Campagne

Sylwia Huber

Sonja Meier

Angelique Augustin

Tobias Heckel

Helene 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 Clery

Sergey Paushkin

Adrian R Krainer

Frederic H-T Allain

Friedrich Metzger

Affiliations

Soon will be listed here.

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.

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