TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy.

Abstract

Prevention of skipping of exon 7 during pre-mRNA splicing of Survival Motor Neuron 2 (SMN2) holds the promise for cure of spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Here, we report T-cell-restricted intracellular antigen 1 (TIA1) and TIA1-related (TIAR) proteins as intron-associated positive regulators of SMN2 exon 7 splicing. We show that TIA1/TIAR stimulate exon recognition in an entirely novel context in which intronic U-rich motifs are separated from the 5' splice site by overlapping inhibitory elements. TIA1 and TIAR are modular proteins with three N-terminal RNA recognition motifs (RRMs) and a C-terminal glutamine-rich (Q-rich) domain. Our results reveal that any one RRM in combination with a Q domain is necessary and sufficient for TIA1-associated regulation of SMN2 exon 7 splicing in vivo. We also show that increased expression of TIA1 counteracts the inhibitory effect of polypyrimidine tract binding protein, a ubiquitously expressed factor recently implicated in regulation of SMN exon 7 splicing. Our findings expand the scope of TIA1/TIAR in genome-wide regulation of alternative splicing under normal and pathological conditions.

• Authors: Natalia N Singh, Joonbae Seo, Eric W Ottesen, Maria Shishimorova, Dhruva Bhattacharya, Ravindra N Singh
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 31 Issue 5 Pg. 935-54 (Mar 2011) ISSN: 1098-5549 [Electronic] United States
• PMID: 21189287 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Poly(A)-Binding Proteins
• RNA-Binding Proteins
• SMN2 protein, human
• Survival of Motor Neuron 2 Protein
• T-Cell Intracellular Antigen-1
• TIA1 protein, human
• Polypyrimidine Tract-Binding Protein
• TIAL1 protein, human

Topics

• Alternative Splicing
• Cell Line
• Exons
• Humans
• Introns
• Muscular Atrophy, Spinal (genetics)
• Poly(A)-Binding Proteins (genetics, metabolism)
• Polypyrimidine Tract-Binding Protein (antagonists & inhibitors)
• RNA-Binding Proteins (genetics, metabolism)
• Survival of Motor Neuron 2 Protein (genetics, metabolism)
• T-Cell Intracellular Antigen-1