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Antagonistic factors control the unproductive splicing of SC35 terminal intron.

Natacha Dreumont, Sara Hardy, Isabelle Behm-Ansmant, Liliane Kister, Christiane Branlant, James Stevenin, and Cyril F Bourgeois (2010)

Nucleic Acids Res, 38(4):1353-66.

Alternative splicing is regulated in part by variations in the relative concentrations of a variety of factors, including serine/arginine-rich (SR) proteins. The SR protein SC35 self-regulates its expression by stimulating unproductive splicing events in the 3' untranslated region of its own pre-mRNA. Using various minigene constructs containing the terminal retained intron and flanking exons, we identified in the highly conserved last exon a number of exonic splicing enhancer elements responding specifically to SC35, and showed aninverse correlation between affinity of SC35 and enhancer strength. The enhancerregion, which is included in a long stem loop, also contains repressor elements,and is recognized by other RNA-binding proteins, notably hnRNP H protein and TARDNA binding protein (TDP-43). Finally, in vitro and in cellulo experiments indicated that hnRNP H and TDP-43 antagonize the binding of SC35 to the terminalexon and specifically repress the use of SC35 terminal 3' splice site. Our studyprovides new information about the molecular mechanisms of SC35-mediated splicing activation. It also highlights the existence of a complex network of self- and cross-regulatory mechanisms between splicing regulators, which controls their homeostasis and offers many ways of modulating their concentration in response to the cellular environment.

 
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