These findings suggest not only that the SF3B1–SUGP1 heterodimer structure that we modeled (and experimentally validated) is indeed compatible with DHX15 binding to form a larger complex but also that the binding of SF3B1 to SUGP1 in two separate regions (both subject to multiple cancer-associated mutations) functions to “loop out” the SUGP1 G-patch for interaction with DHX15. Here, SF3B1 is linked to cancer.