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

Sivaramakrishnan, M., McCarthy, K. D., Campagne, S., Huber, S., Meier, S., Augustin, A., Heckel, T., Meistermann, H., Hug, M. N., Birrer, P., Moursy, A., Khawaja, S., Schmucki, R., Berntenis, N., Giroud, N., Golling, S., Tzouros, M., Banfai, B., Duran-Pacheco, G., Lamerz, J., Hsiu Liu, Y., Luebbers, T., Ratni, H., Ebeling, M., Clery, A., Paushkin, S., Krainer, A. R., Allain, F. H., Metzger, F. (November 2017) Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat Commun, 8 (1). p. 1476. ISSN 2041-1723

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URL: https://www.ncbi.nlm.nih.gov/pubmed/29133793

DOI: 10.1038/s41467-017-01559-4

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.

Item Type:	Paper
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > pre-mRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy
CSHL Authors:	Krainer, Adrian R. Liu, Ying Hsiu
Communities:	CSHL labs > Krainer lab
Depositing User:	Matt Covey
Date:	14 November 2017
Date Deposited:	27 Nov 2017 21:50
Last Modified:	14 Dec 2017 19:55
PMCID:	PMC5684323
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/35671

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