BS recognition in SF3B1 wild-type and SF3B1-mutant cells. (Left) Under normal conditions, the WT SF3B1 spliceosome is associated with SUGP1, which activates the helicase activity of DHX15 via its G-patch domain (G), thereby allowing the usage of the canonical BP and 3′ss for splicing. (Right) When specific residues of the SF3B1 HD are mutated in cancer, interaction of SF3B1 with SUGP1 is disrupted, leading to loss of SUGP1 during spliceosome assembly. In the absence of SUGP1, DHX15 is not activated, and SF1 is not efficiently displaced from the canonical BS thus blocking its recognition by the U2snRNP. The SF3B1 mutant spliceosome must then recognize an upstream BS and select a cryptic 3′ss. (Figure modified from Zhang et al. 2019.)
