The RNA Binding Protein hnRNP Q Modulates the Utilization of Exon 7 in the Survival Motor Neuron 2 (SMN2) Gene
Copyright policy )The RNA Binding Protein hnRNP Q Modulates the Utilization of Exon 7 in the Survival Motor Neuron 2 (SMN2) Gene
Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The human SMN2 gene has a C-to-T transition at position +6 of exon 7 and thus produces exon 7-skipping mRNAs. However, we observed an unexpectedly high level of exon 7-containing SMN2 transcripts as well as SMN protein in testis of smn(-/-) SMN2 transgenic mice. Using affinity chromatography, we identified several SMN RNA-associating proteins in mouse testis and human HeLa cells, including hnRNP Q. The major hnRNP Q isoform, Q1, directly bound SMN exon 7 in the vicinity of nucleotide +6. Overexpression of hnRNP Q1 promoted the inclusion of exon 7 in SMN2, probably by activating the use of its upstream 3' splice site. However, the minor isoforms Q2/Q3 could antagonize the activity of hnRNP Q1 and induced exon 7 exclusion. Intriguingly, enhanced exon 7 inclusion was also observed upon concomitant depletion of three hnRNP Q isoforms. Thus, differential expression of hnRNP Q isoforms may result in intricate control of SMN precursor mRNA splicing. Here, we demonstrate that hnRNP Q is a splicing modulator of SMN, further underscoring the potential of hnRNP Q as a therapeutic target for SMA.
- National Tsing Hua University Taiwan
- Kaohsiung Medical University Taiwan
- University System of Taiwan Taiwan
- Chung Hua University Taiwan
- Academia Sinica Taiwan
Male, Mice, Knockout, Base Sequence, Molecular Sequence Data, RNA-Binding Proteins, Nerve Tissue Proteins, SMN Complex Proteins, Exons, Heterogeneous-Nuclear Ribonucleoproteins, Recombinant Proteins, Cell Line, Muscular Atrophy, Spinal, Alternative Splicing, Mice, Liver, RNA Precursors, Animals, Humans, Protein Isoforms, Cyclic AMP Response Element-Binding Protein
Male, Mice, Knockout, Base Sequence, Molecular Sequence Data, RNA-Binding Proteins, Nerve Tissue Proteins, SMN Complex Proteins, Exons, Heterogeneous-Nuclear Ribonucleoproteins, Recombinant Proteins, Cell Line, Muscular Atrophy, Spinal, Alternative Splicing, Mice, Liver, RNA Precursors, Animals, Humans, Protein Isoforms, Cyclic AMP Response Element-Binding Protein
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