Figure 2. Components of the core and regulatory splicing machinery that exhibit alterations in human tumors.

(A) Graphical representation of the stepwise assembly of spliceosomal complexes on a pre-mRNA molecule and catalysis of the splicing reaction to generate mature spliced mRNA. First, the ATP-independent binding of U1 snRNP to the 5′ splice site (5′SS) of the intron initiate the assembly of the “Early” or E complex on the pre-mRNA. In addition, SF1 and U2AF2 bind respectively to the branch point site (BPS) and the polypyrimidine tract (Py-tract). In the second step, the ATP-dependent interaction of U2 snRNP with the BPS leads to the formation of the A complex. This interaction is stabilized by the SF3a and SF3b protein complexes, as well as U2AF2 and U2AF1, and leads the displacement of SF1 from the BPS. Recruitment of the pre-assembled U4/U6/U5 tri-snRNP marks the formation of the catalytically inactive B complex. Major conformational changes, including release of U1 and U4, lead to spliceosome activation and formation of the B* complex. The first catalytic step of splicing, generates the C complex and results in the formation of the lariat. Complex C performs the second catalytic step of splicing, which results in the joining of the two exons. Post-splicing the spliceosome disassembles in an orderly manner, releasing the mRNA, as well as the lariat bound by U2/U5/U6. The snRNP are then further dissociated and recycled. (B) Spliceosomal core factors that exhibit recurrent somatic mutations in human tumors are listed next each complex (colored boxes) and are shown in more details for complexes E and A (right panels). In addition to core splicing factors, regulatory splicing factors (SF) that can bind to exonic or intronic splicing enhancer (ESE or ISE) or silencer (ESS or ISS) sequences to fine-tune splicing are also found altered in human tumors (grey boxes).