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Nucleic Acids Research Advance Access published online on September 22, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp778
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

An Alu-derived intronic splicing enhancer facilitates intronic processing and modulates aberrant splicing in ATM

Tibor Pastor, Gabriele Talotti, Marzena Anna Lewandowska and Franco Pagani*

International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy

*To whom correspondence should be addressed. Tel: +39 40 375 7342; Fax: +39 40 226 555; Email: pagani{at}icgeb.org

Received August 3, 2009. Revised September 1, 2009. Accepted September 2, 2009.

We have previously reported a natural GTAA deletion within an intronic splicing processing element (ISPE) of the ataxia telangiectasia mutated (ATM) gene that disrupts a non-canonical U1 snRNP interaction and activates the excision of the upstream portion of the intron. The resulting pre-mRNA splicing intermediate is then processed to a cryptic exon, whose aberrant inclusion in the final mRNA is responsible for ataxia telangiectasia. We show here that the last 40 bases of a downstream intronic antisense Alu repeat are required for the activation of the cryptic exon by the ISPE deletion. Evaluation of the pre-mRNA splicing intermediate by a hybrid minigene assay indicates that the identified intronic splicing enhancer represents a novel class of enhancers that facilitates processing of splicing intermediates possibly by recruiting U1 snRNP to defective donor sites. In the absence of this element, the splicing intermediate accumulates and is not further processed to generate the cryptic exon. Our results indicate that Alu-derived sequences can provide intronic splicing regulatory elements that facilitate pre-mRNA processing and potentially affect the severity of disease-causing splicing mutations.


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