Campus Units

Biomedical Sciences

Document Type

Article

Publication Version

Published Version

Publication Date

2011

Journal or Book Title

Molecular and Cellular Biology

Volume

31

Issue

5

First Page

935

Last Page

954

DOI

10.1128/MCB.00945-10

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

Comments

This is an article from Molecular and Cellular Biology 31 (2011): 935, doi:10.1128/MCB.00945-10. Posted with permission.

Copyright Owner

American Society for Microbiology

Language

en

File Format

application/pdf

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