Cooperation and Competition of RNA Secondary Structure and RNA-Protein Interactions in the Regulation of Alternative Splicing

Abstract

The regulation of alternative splicing in eukaryotic cells is carried out through the coordinated action of a large number of factors, including RNA-binding proteins and RNA structure. The RNA structure influences alternative splicing by blocking cis-regulatory elements, or bringing them closer or farther apart. In combination with RNA-binding proteins, it generates transcript conformations that help to achieve the necessary splicing outcome. However, the binding of regulatory proteins depends on RNA structure and, vice versa, the formation of RNA structure depends on the interaction with regulators. Therefore, RNA structure and RNA-binding proteins are inseparable components of common regulatory mechanisms. This review highlights examples of alternative splicing regulation by RNA-binding proteins, the regulation through local and long-range RNA structures, as well as how these elements work together, cooperate, and compete.

Keywords: RNA structure; RNA-binding proteins; long-range interactions; regulation; splicing.

Fig. 1

Blockage of cis-regulatory splicing elements by RNA structure. (A) Blockage of a splice site; (B) blockage of an intronic splicing enhancer; (C) blockage of an intronic splicing silencer. Red and green lines indicate the activating and inhibitory effects on splicing, respectively

Fig. 2

Spatial segregation of cis-regulatory splicing elements by RNA structure (RNA “bridges”). (A) Bringing splice sites closer together. (B) Bringing a splicing enhancer closer to the splice site

Fig. 3

Spatial separation of cis-regulatory splicing elements by the RNA structure (loop-outs). (A) Looping out a region containing one or more exons. (B) Back-splicing in an intron leading to the formation of a circular RNA. Red and green lines indicate the activating and inhibitory effects on splicing, respectively

Fig. 4

The combined effect of RNA secondary structure and RNA-protein interactions. (A) Creation of a splice site through RNA editing (A-to-I RNA editing). (B) Binding of an RNA-binding protein to a stem-loop structure. (C) Binding of an RNA-binding protein to a double-stranded region