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Mol Cell. 2013 Mar 7;49(5):972-82. doi: 10.1016/j.molcel.2012.12.025. Epub 2013 Feb 7.

hnRNP L and hnRNP A1 induce extended U1 snRNA interactions with an exon to repress spliceosome assembly.

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1
Department of Biochemistry and Biophysics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104-6059, USA.

Abstract

Pre-mRNA splicing is catalyzed through the activity of the spliceosome, a dynamic enzymatic complex. Forcing aberrant interactions within the spliceosome can reduce splicing efficiency and alter splice site choice; however, it is unknown whether such alterations are naturally exploited mechanisms of splicing regulation. Here, we demonstrate that hnRNP L represses CD45 exon 4 by recruiting hnRNP A1 to a sequence upstream of the 5' splice site. Together, hnRNP L and A1 induce extended contacts between the 5' splice site-bound U1 snRNA and neighboring exonic sequences that, in turn, inhibit stable association of U6 snRNA and subsequent catalysis. Importantly, analysis of several exons regulated by hnRNP L shows a clear relationship between the potential for binding of hnRNP A1 and U1 snRNA and the effect of hnRNP L on splicing. Together, our results demonstrate that conformational perturbations within the spliceosome are a naturally occurring and generalizable mechanism for controlling alternative splicing decisions.

PMID:
23394998
PMCID:
PMC3595347
DOI:
10.1016/j.molcel.2012.12.025
[Indexed for MEDLINE]
Free PMC Article
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