The University of Southampton
University of Southampton Institutional Repository

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

Compensatory signals associated with the activation of human GC 5' splice sites
Compensatory signals associated with the activation of human GC 5' splice sites
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
0305-1048
7077-7091
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Hwang, Gyulin
f4b0347f-a35b-4e0c-938f-be2e5b40cb54
Asplund, A. Charlotta
63d41df6-689c-47d0-a217-365686dc5332
Churbanov, Alexander
3ef4f6a4-211f-418c-9c4f-7b88de55da12
Smith, C.I. Edvard
813270cc-54ac-4f87-bd77-a40838b11e70
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Hwang, Gyulin
f4b0347f-a35b-4e0c-938f-be2e5b40cb54
Asplund, A. Charlotta
63d41df6-689c-47d0-a217-365686dc5332
Churbanov, Alexander
3ef4f6a4-211f-418c-9c4f-7b88de55da12
Smith, C.I. Edvard
813270cc-54ac-4f87-bd77-a40838b11e70
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e

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), 7077-7091. (doi:10.1093/nar/gkr306).

Record type: Article

Abstract

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

This record has no associated files available for download.

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
ORCID for Igor Vorechovsky: ORCID iD orcid.org/0000-0002-6740-6502

Catalogue record

Date deposited: 26 May 2011 14:09
Last modified: 15 Mar 2024 03:16

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×