Context-Dependent Regulatory Mechanism of the Splicing Factor hnRNP L

• DOI: 10.1016/j.molcel.2009.12.027
• Publication Date: 2010-01-29T11:59:50Z
• Authors: Laura B. Motta-Mena; Florian Heyd; Kristen W. Lynch
• Keywords: splice; Heterogeneous nuclear ribonucleoprotein; Splice site mutation; Exonic splicing enhancer

Splicing regulatory proteins often have distinct activities when bound to exons versus introns. However, less clear is whether variables aside from location can influence activity. HnRNP L binds to a motif present in both CD45 variable exons 4 and 5 to affect their coordinate repression. Here, we show that, in contrast to its direct repression of exon 4, hnRNP L represses exon 5 by countering the activity of a neighboring splicing enhancer. In the absence of the enhancer, hnRNP L unexpectedly activates exon inclusion. As the splice sites flanking exon 4 and 5 are distinct, we directly examined the effect of varying splice site strength on the mechanism of hnRNP L function. Remarkably, binding of hnRNP L to an exon represses strong splice sites but enhances weak splice sites. A model in which hnRNP L stabilizes snRNP binding can explain both effects in a manner determined by the inherent snRNP-substrate affinity.