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Molecular and Cellular Biology, June 2000, p. 3988-3995, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

A 5' Splice Site-Proximal Enhancer Binds SF1 and Activates Exon Bridging of a Microexon

Troy Carlo,1,2,dagger Rebecca Sierra,1 and Susan M. Berget1,2,*

Verna and Marrs McLean Department of Biochemistry1 and Program in Cell and Molecular Biology,2 Baylor College of Medicine, Houston, Texas 77030

Received 14 July 1999/Returned for modification 25 August 1999/Accepted 15 March 2000

Internal exon size in vertebrates occurs over a narrow size range. Experimentally, exons shorter than 50 nucleotides are poorly included in mRNA unless accompanied by strengthened splice sites or accessory sequences that act as splicing enhancers, suggesting steric interference between snRNPs and other splicing factors binding simultaneously to the 3' and 5' splice sites of microexons. Despite these problems, very small naturally occurring exons exist. Here we studied the factors and mechanism involved in recognizing a constitutively included six-nucleotide exon from the cardiac troponin T gene. Inclusion of this exon is dependent on an enhancer located downstream of the 5' splice site. This enhancer contains six copies of the simple sequence GGGGCUG. The enhancer activates heterologous microexons and will work when located either upstream or downstream of the target exon, suggesting an ability to bind factors that bridge splicing units. A single copy of this sequence is sufficient for in vivo exon inclusion and is the binding site for the known bridging mammalian splicing factor 1 (SF1). The enhancer and its bound SF1 act to increase recognition of the upstream exon during exon definition, such that competition of in vitro reactions with RNAs containing the GGGGCUG repeated sequence depress splicing of the upstream intron, assembly of the spliceosome on the 3' splice site of the exon, and cross-linking of SF1. These results suggest a model in which SF1 bridges the small exon during initial assembly, thereby effectively extending the domain of the exon.

* Corresponding author. Mailing address: Verna and Marrs McLean Department of Biochemistry and Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-5758. Fax: (713) 795-5487. E-mail: sberget{at}bcm.tmc.edu.

dagger Present address: Department of Biology, Brandeis University, Waltham, MA 02254-9110.

Molecular and Cellular Biology, June 2000, p. 3988-3995, Vol. 20, No. 11
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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