Nucleic Acids Research Advance Access published online on August 7, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm569
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Tissue-specific splicing regulator Fox-1 induces exon skipping by interfering E complex formation on the downstream intron of human F1
gene
1Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodaicho, Nadaku, Kobe 657-8501, 2Biological Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064 and 3Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan
*To whom correspondence should be addressed. Tel: +81 78 803 5725; Fax: +81 78 803 5725; Email: kunio{at}kobe-u.ac.jp
Received March 28, 2007. Revised June 27, 2007. Accepted July 12, 2007.
Fox-1 is a regulator of tissue-specific splicing, via binding to the element (U)GCAUG in mRNA precursors, in muscles and neuronal cells. Fox-1 can regulate splicing positively or negatively, most likely depending on where it binds relative to the regulated exon. In cases where the (U)GCAUG element lies in an intron upstream of the alternative exon, Fox-1 protein functions as a splicing repressor to induce exon skipping. Here we report the mechanism of exon skipping regulated by Fox-1, using the hF1
gene as a model system. We found that Fox-1 induces exon 9 skipping by repressing splicing of the downstream intron 9 via binding to the GCAUG repressor elements located in the upstream intron 8. In vitro splicing analyses showed that Fox-1 prevents formation of the pre-spliceosomal early (E) complex on intron 9. In addition, we located a region of the Fox-1 protein that is required for inducing exon skipping. Taken together, our data show a novel mechanism of how RNA-binding proteins regulate alternative splicing.
Present address: Yui Jin, Life Sciences Institute, University of Michigan, MI 48109, USA Naoyuki Kataoka, Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan
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