Journal
RNA BIOLOGY
Volume 7, Issue 1, Pages 56-64Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/rna.7.1.10402
Keywords
splicing; alternative splicing; silencer; hnRNP; snRNP
Categories
Funding
- Deutsche Forschungsgemeinschaft [316/10, 316/12]
- Federal Ministry for Education and Research [NGNF-2]
- EuropeanCommission
- Shanghai Municipal Council for Science and Technology [09PJ1411000]
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Heterogeneous nuclear ribonucleoprotein (hnRNP) L can regulate alternative mRNA splicing in diverse ways, binding to exonic or intronic sites and acting as either an activator or repressor. To investigate the mechanistic basis of hnRNP L-regulated alternative splicing, we focus here on two specific cases of hnRNP L-dependent splice site recognition. First, in the case of TJP1 our microarray data had suggested that exon 20 inclusion is regulated by hnRNP L as a repressor. Here we demonstrate by mutational analysis that exon skipping is mediated by a short silencer sequence consisting of three hnRNP L high-score binding motifs located upstream of the 3' splice site of the regulated exon. UV crosslinking and immunoprecipitation experiments showed that hnRNP L binding interferes with 3' splice site recognition by U2AF65. Second, SLC2A2 contains a CA-repeat sequence close to the 5' splice site of the regulated exon 4. Using psoralen crosslinking, we demonstrate that hnRNP L represses splicing by preventing 5' splice site recognition of the U1 snRNP. In sum, our data provide new insights into the mechanisms of how hnRNP L-bound to intronic sites-regulates exon recognition.
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