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A combinatorial code for splicing silencing: UAGG and GGGG motifs

Han, K and Yeo, G and An, P and Burge, CB and Grabowski, PJ (2005) A combinatorial code for splicing silencing: UAGG and GGGG motifs. PLoS Biology, 3 (5). 0843 - 0860. ISSN 1544-9173

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Alternative pre-mRNA splicing is widely used to regulate gene expression by tuning the levels of tissue-specific mRNA isoforms. Few regulatory mechanisms are understood at the level of combinatorial control despite numerous sequences, distinct from splice sites, that have been shown to play roles in splicing enhancement or silencing. Here we use molecular approaches to identify a ternary combination of exonic UAGG and 5′-splice-site-proximal GGGG motifs that functions cooperatively to silence the brain-region-specific CI cassette exon (exon 19) of the glutamate NMDA R1 receptor (GRIN1) transcript. Disruption of three components of the motif pattern converted the CI cassette into a constitutive exon, while predominant skipping was conferred when the same components were introduced, de novo, into a heterologous constitutive exon. Predominant exon silencing was directed by the motif pattern in the presence of six competing exonic splicing enhancers, and this effect was retained after systematically repositioning the two exonic UAGGs within the CI cassette. In this system, hnRNP A1 was shown to mediate silencing while hnRNP H antagonized silencing. Genome-wide computational analysis combined with RT-PCR testing showed that a class of skipped human and mouse exons can be identified by searches that preserve the sequence and spatial configuration of the UAGG and GGGG motifs. This analysis suggests that the multi-component silencing code may play an important role in the tissue-specific regulation of the CI cassette exon, and that it may serve more generally as a molecular language to allow for intricate adjustments and the coordination of splicing patterns from different genes. © 2005 Han et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Han, K
Yeo, G
An, Ppia1@pitt.eduPIA10000-0002-3080-2288
Burge, CB
Grabowski, PJpag4@pitt.eduPAG40000-0003-1881-6190
Date: 1 January 2005
Date Type: Publication
Journal or Publication Title: PLoS Biology
Volume: 3
Number: 5
Page Range: 0843 - 0860
DOI or Unique Handle: 10.1371/journal.pbio.0030158
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Refereed: Yes
ISSN: 1544-9173
PubMed Central ID: 15828859
Date Deposited: 11 Jul 2012 18:05
Last Modified: 13 Apr 2019 14:55


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