SR Proteins: Binders, Regulators, and Connectors of RNA

Abstract

Serine and arginine-rich (SR) proteins are RNA-binding proteins (RBPs) known as constitutive and alternative splicing regulators. As splicing is linked to transcriptional and post-transcriptional steps, SR proteins are implicated in the regulation of multiple aspects of the gene expression program. Recent global analyses of SR-RNA interaction maps have advanced our understanding of SR-regulated gene expression. Diverse SR proteins play partially overlapping but distinct roles in transcription-coupled splicing and mRNA processing in the nucleus. In addition, shuttling SR proteins act as adaptors for mRNA export and as regulators for translation in the cytoplasm. This mini-review will summarize the roles of SR proteins as RNA binders, regulators, and connectors from transcription in the nucleus to translation in the cytoplasm.

Keywords: RNA-binding proteins; SR proteins; export; splicing; transcription; translation.

Fig. 1. List and domains of SR proteins

The domain structures (RRM, RRMH, RS, and Zn) are denoted as shown in the lower box. Current names for SR proteins are SRSFs, but aliases are also indicated in the parenthesis. Among 12 core SR proteins, 6 (red letters) are reported to shuttle between nucleus and cytoplasm (shuttling SR proteins), whereas the others (black letters) have not been shown to have shuttling activity (non-shuttling SR proteins), as indicated in the upper box.

Fig. 2. Outline of techniques used for identification of SR protein-binding RNA elements

(A) SELEX (systematic evolution of ligands by exponential enrichment) for in vitro identification of SR-binding RNA motifs. A random RNA library was used for the selection of binding RNA sequences. (B) Functional SELEX. Reporter-based in vitro and in vivo identification of splicing regulatory elements. ESEs (Exonic Splicing Enhancers) can be selected in the reporter as shown here. (C) CLIP-Seq (Cross-linking and immunoprecipitation-sequencing) for global identification of SR-binding motifs in target RNAs.

Fig. 3. Multiple roles of SR proteins during gene expression from the nucleus to the cytoplasm

(A) Transcription-coupled splicing in chromatin. Transcription elongation and splicing are regulated by Pol II phosphorylation, histone modification, and SR–protein interactions. More SR proteins (shown in different colors) are recruited, and spliceosome assembly occurs on nascent pre-mRNP. Storage and assembly of splicing machinery in speckles is also shown. (B) mRNA export from the nucleus to cytoplasm. Export receptor (NXF) is recruited to export adaptor SR-bound mRNA. (C) Translational regulation in the cytoplasm.