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Compensatory signals associated with the activation of human GC 5' splice sites

Record type: Article

GC 5? splice sites (5?ss) are present in ?1% of human introns, but factors promoting their efficient selection are poorly understood. Here, we describe a case of X-linked agammaglobulinemia resulting from a GC 5?ss activated by a mutation in BTK intron 3. This GC 5?ss was intrinsically weak, yet it was selected in >90% primary transcripts in the presence of a strong and intact natural GT counterpart. We show that efficient selection of this GC 5?ss required a high density of GAA/CAA-containing splicing enhancers in the exonized segment and was promoted by SR proteins 9G8, Tra2? and SC35. The GC 5?ss was efficiently inhibited by splice-switching oligonucleotides targeting either the GC 5?ss itself or the enhancer. Comprehensive analysis of natural GC-AG introns and previously reported pathogenic GC 5?ss showed that their efficient activation was facilitated by higher densities of splicing enhancers and lower densities of silencers than their GT 5?ss equivalents. Removal of the GC-AG introns was promoted to a minor extent by the splice-site strength of adjacent exons and inhibited by flanking Alu repeats, with the first downstream Alus located on average at a longer distance from the GC 5?ss than other transposable elements. These results provide new insights into the splicing code that governs selection of noncanonical splice sites

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Citation

Kralovicova, Jana, Hwang, Gyulin, Asplund, A. Charlotta, Churbanov, Alexander, Smith, C.I. Edvard and Vorechovsky, Igor (2011) Compensatory signals associated with the activation of human GC 5' splice sites Nucleic Acids Research, 39, (16), pp. 7077-7091. (doi:10.1093/nar/gkr306).

More information

Accepted/In Press date: 23 May 2011
Published date: 1 September 2011
Organisations: Human Genetics, Biological Sciences

Identifiers

Local EPrints ID: 188679
URI: http://eprints.soton.ac.uk/id/eprint/188679
ISSN: 0305-1048
PURE UUID: d5345e89-74b6-412c-9410-0a33c09a8fc8

Catalogue record

Date deposited: 26 May 2011 14:09
Last modified: 18 Jul 2017 11:42

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Contributors

Author: Jana Kralovicova
Author: Gyulin Hwang
Author: A. Charlotta Asplund
Author: Alexander Churbanov
Author: C.I. Edvard Smith

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