| First Author | Singh NN | Year | 2011 |
| Journal | Mol Cell Biol | Volume | 31 |
| Issue | 5 | Pages | 935-54 |
| PubMed ID | 21189287 | Mgi Jnum | J:169182 |
| Mgi Id | MGI:4939983 | Doi | 10.1128/MCB.00945-10 |
| Citation | Singh NN, et al. (2011) TIA1 Prevents Skipping of a Critical Exon Associated with Spinal Muscular Atrophy. Mol Cell Biol 31(5):935-54 |
| abstractText | 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. |
