Figure 7.

Spliceosome activities and Mcl1 regulation summary. The U1 spliceosome subunit is recruited to the 5′ splice donor site at introns to form complex E. The U2 subunit (including SF3B) is subsequently recruited to form complex A, followed by recruitment of the U5-U4/U6 subunits (that includes Prpf8, Ubl5 and Sart1) generating complex B. The first transesterification reaction then occurs generating a lariat and releasing the U1 and U4 subunits. The second transesterification reaction occurs generating the mature mRNA by ligating the adjacent exons and releasing the remaining spliceosome subunits for recycling and the excised intron for degradation. SSA binds SF3B and delays progression from complex A to complex B, and SSA treatment or knockdown of the complex B subunits PRPF8, UBL5 or SART1 increase pro-apoptotic Mcl1-S splicing, decrease translation of antiapoptotic Mcl1-L protein and blocks the Mcl1 survival bias in Mcl1-dependent tumors, restoring sensitization to Bcl2 antagonists, such as ABT-737. BN82685 inhibits the second transesterification reaction and does not share this phenotype