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Molecular and Cellular Biology, August 2005, p. 6912-6920, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.6912-6920.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of Splicing Silencers and Enhancers in Sense Alus: a Role for Pseudoacceptors in Splice Site Repression

Haixin Lei^1,2 and Igor Voechovsk^1*

University of Southampton School of Medicine, Division of Human Genetics, Southampton SO16 6YD, United Kingdom,¹ Karolinska Institute at NOVUM, Department of Biosciences, S-141 57 Huddinge, Sweden²

Received 26 February 2005/ Returned for modification 31 March 2005/ Accepted 27 May 2005

Auxiliary splicing signals in introns play an important role in splice site selection, but these elements are poorly understood. We show that a subset of serine/arginine (SR)-rich proteins activate a cryptic 3' splice site in a sense Alu repeat located in intron 4 of the human LST1 gene. Utilization of this cryptic splice site is controlled by juxtaposed Alu-derived splicing silencers and enhancers between closely linked short tandem repeats TNFd and TNFe. Systematic mutagenesis of these elements showed that AG dinucleotides that were not preceded by purine residues were critical for repressing exon inclusion of a chimeric splicing reporter. Since the splice acceptor-like sequences are present in excess in exonic splicing silencers, these signals may contribute to inhibition of a large number of pseudosites in primate genomes.

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