How RNA structure dictates the usage of a critical exon of spinal muscular atrophy gene

Role of RNA structure in pre-mRNA splicing has been implicated for several critical exons associated with genetic disorders. However, much of the structural studies linked to pre-mRNA splicing regulation are limited to terminal stem-loop structures (hairpins) sequestering splice sites. In few instan...

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Published in:Biochimica et biophysica acta. Gene regulatory mechanisms 2019-11, Vol.1862 (11-12), p.194403-194403, Article 194403
Main Authors: Singh, Natalia N., Singh, Ravindra N.
Format: Article
Language:English
Subjects:
Alu Elements
Exons
Gene Expression Regulation
Humans
ISS-N1
Models, Molecular
Muscular Atrophy, Spinal - genetics
Nucleic Acid Conformation
RNA Splicing
RNA structure
RNA, Circular - genetics
RNA, Messenger - chemistry
RNA, Messenger - metabolism
SMA
Small molecule
SMN
Splicing
Survival of Motor Neuron 2 Protein - chemistry
Survival of Motor Neuron 2 Protein - genetics
U1 snRNP
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Summary:Role of RNA structure in pre-mRNA splicing has been implicated for several critical exons associated with genetic disorders. However, much of the structural studies linked to pre-mRNA splicing regulation are limited to terminal stem-loop structures (hairpins) sequestering splice sites. In few instances, role of long-distance interactions is implicated as the major determinant of splicing regulation. With the recent surge of reports of circular RNA (circRNAs) generated by backsplicing, role of Alu-associated RNA structures formed by long-range interactions are taking central stage. Humans contain two nearly identical copies of Survival Motor Neuron (SMN) genes, SMN1 and SMN2. Deletion or mutation of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1 due to exon 7 skipping causes spinal muscular atrophy (SMA), one of the leading genetic diseases of children. In this review, we describe how structural elements formed by both local and long-distance interactions are being exploited to modulate SMN2 exon 7 splicing as a potential therapy for SMA. We also discuss how Alu-associated secondary structure modulates generation of a vast repertoire of SMN circRNAs. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.
ISSN:1874-9399
1876-4320
DOI:10.1016/j.bbagrm.2019.07.004