Impairment of pre-mRNA splicing in liver disease: Mechanisms and consequences

Figure 1 Splicing consensus sequences and interactions with small nuclear ribonucleoproteins (snRNPs), SR proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs). A: Arrangement of donor and acceptor sites in a eukaryotic gene and interaction with snRNPs during splicing. Core elements necessary for pre-mRNA splicing include the 5’ and 3’ splice sites and a branch point sequence and a polypyrimidine-rich tract located upstream of the 3’ splice site. The splicing factor U2AF (U2 auxiliary factor) consists of two subunits which bind to the 3’ splice site and the polypyrimidine tract. U2AF promotes the binding of U2 snRNA in the U2 snRNP complex to the branch site. The U1 snRNP particle binds to the upstream and downstream 5’ splice sites through base pairing of the U1 snRNA. The additional assembly of the snRNPs U4, U5 and U6 is required for the constitution of the spliceosome and the removal of introns; B: Interaction of splicing regulatory proteins with exonic and intronic target sequences. SR (Ser-Arg) proteins bind to exonic splicing enhancers (ESEs) to stimulate the binding of U2AF to a weak 3’ splice site, which here is interrupted by purines (R). They also stimulate the binding of the U1 snRNP to the downstream 5’ splice site. SR proteins antagonise the negative effect on splicing of hnRNPs bound to exonic splicing silencers (ESSs). In many cases, U-rich sequences situated immediately downstream of 5’ splice sites known as intronic splicing enhancers (ISEs) are bound by factors such as T cell-restricted intracellular antigen 1 (TIA1) to facilitate U1 binding.

Figure 2 Different modes of alternative splicing. After pre-mRNA processing a single gene can encode multiple mRNA isoforms that possess distinct coding and regulatory sequences. Alternative splicing isoforms can result from: 1: The skipping or inclusion of alternative exons; 2: The selection of alternative 5’; or 3: 3’ splice sites (SS); 4: The inclusion of introns; 5: The selection of different polyadenylation sites [AAA(n)]; and 6: The transcriptional initiation at an alternative promoter associated with the inclusion of specific exons.