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Molecular and Cellular Biology, August 2005, p. 7323-7332, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7323-7332.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Exon Inclusion Is Dependent on Predictable Exonic Splicing Enhancers

Xiang H.-F. Zhang, Thaned Kangsamaksin, Mann S. P. Chao, Joydeep K. Banerjee, and Lawrence A. Chasin*

Department of Biological Sciences, Columbia University, New York, New York 10027

Received 1 March 2005/ Returned for modification 25 March 2005/ Accepted 16 May 2005

We have previously formulated a list of approximately 2,000 RNA octamers as putative exonic splicing enhancers (PESEs) based on a statistical comparison of human exonic and nonexonic sequences (X. H. Zhang and L. A. Chasin, Genes Dev. 18:1241-1250, 2004). When inserted into a poorly spliced test exon, all eight tested octamers stimulated splicing, a result consistent with their identification as exonic splicing enhancers (ESEs). Here we present a much more stringent test of the validity of this list of PESEs. Twenty-two naturally occurring examples of nonoverlapping PESEs or PESE clusters were identified in six mammalian exons; five of the six exons tested are constitutively spliced. Each of the 22 individual PESEs or PESE clusters was disrupted by site-directed mutagenesis, usually by a single-base substitution. Eighteen of the 22 disruptions (82%) resulted in decreased splicing efficiency. In contrast, 24 control mutations had little or no effect on splicing. This high rate of success suggests that most PESEs function as ESEs in their natural context. Like most exons, these exons contain several PESEs. Since knocking out any one of several could produce a severalfold decrease in splicing efficiency, we conclude that there is little redundancy among ESEs in an exon and that they must work in concert to optimize splicing.

* Corresponding author: Department of Biological Sciences, Columbia University, 1212 Amsterdam Ave., MC 2433, New York, NY 10027. Phone: (212) 854-4645. Fax: (212) 531-0425. E-mail: lac2{at}columbia.edu.

Molecular and Cellular Biology, August 2005, p. 7323-7332, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7323-7332.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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