The Exon Junction Complex: A Multitasking Guardian of the Transcriptome

Abstract

In a recent issue of Molecular Cell, Boehm et al. (2018), Blazquez et al. (2018), and Gonatopoulos-Pournatzis et al. (2018) uncover novel mechanisms by which the cell regulates splicing of cryptic splice sites and microexons.

Figure 1.. The EJC and Auxiliary Factors Regulate Splicing of Cryptic Splice Sites and Microexons

The EJC suppresses usage of cryptic and reconstituted 5′ splice sites (SSs) in a RNPS1-dependent manner. In scenario 1, a cryptic 5′SS downstream of a microexon within Exon 2 is used, resulting in inclusion of the microexon and skipping of Exon 2 in the absence of the EJC. In scenario 2, a reconstituted 5′SS is generated upon ligation of Exons 1 and 2, resulting in re-splicing and skipping of Exon 2 in the absence of the EJC. Additionally, the EJC suppresses cryptic and reconstituted 3′SSs in a RNPS1-independent and EIF4A3-dependent manner. The EJC masks the branchpoint or the polypyrimidine tract of Exon 2, which suppresses usage of the cryptic 3′SS of Exon 3. In the absence of the EJC, the cryptic 3′SS is used and results in Exon 2 skipping. In neurons, SR-related proteins RNPS1 and SRSF11 regulate a program of inclusion of conserved and frame-preserving microexons through interaction with SRRM4, the neuronal-specific SR-repeat protein of 100 kDa (also known as nSR100), at splicing regulatory elements. These interactions promote spliceosome formation. Knockdown of RNPS1, SRSF11, or SRRM4 results in skipping of a neuronal microexon between Exons 1 and 2.