Alternative splicing: regulation without regulators

Abstract

Alternative splicing is typically thought to be controlled by RNA binding proteins that modulate the activity of the spliceosome. A new study not only demonstrates that alternative splicing can be regulated without the involvement of auxiliary splicing factors, but also provides mechanistic insight into how this can occur.

Figure 1

Traditional Splicing Regulation. A. Splicing activators such as SR proteins can function by binding to exonic splicing enhancers (ESEs) where they interact with and recruit U2AF and/or U1 snRNP to the 3′ and 5′ splice sites, respectively. B. Splicing repressors such as hnRNP proteins can inhibit splicing by binding to intronic splicing silencers (ISSs) where they interfere with the binding of U2AF to the 3′ splice site. C. Alternatively hnRNP proteins can bind to ISSs in the introns flanking an exon where they engage in heterophilic interactions and loop out the intervening exon.

Figure 2

Regulation without Regulators. A. In the absence of a splicing silencer, the strong downstream 5′ splice site is used more efficiently than the weak upstream 5′ splice site, despite the fact that U1 snRNP binds to both 5′ splice sites. B. When a splicing silencer (ESS) is present in the exon near the strong downstream 5′ splice site, use of the upstream weak 5′ splice site now predominates. Importantly, the ESS does not prevent U1 snRNP from binding to the strong 5′ splice site, though the configuration in which U1 snRNP interacts is altered. C. When the ESS is present near both 5′ splice sites, it alters the association of U1 snRNP with both 5′ splice sites in the same way. As a result, efficient splicing to the strong downstream 5′ splice site is restored.