Cancer-associated SF3B1 Mutations Inhibit mRNA Nuclear Export by Disrupting SF3B1–THOC5 Interactions

Abstract Mutations in SF3B1 are common in many types of cancer, which promotes cancer progression through aberrant RNA splicing. Recently, mRNA nuclear export has been reported to be defective in cells with SF3B1 K700E mutation. However, the mechanism remains unclear. Our study reveals that the K700E mutation in SF3B1 attenuates its interaction with THOC5, an essential component of mRNA nuclear export complex THO. Furthermore, SF3B1 mutation caused reduced binding of THOC5 with some mRNA and inhibited the nuclear export of these mRNA. Interestingly, THOC5 overexpression restores the nuclear export of these mRNA in cells with SF3B1 K700E mutation. Importantly, other types of cancer-associated SF3B1 mutations also inhibited mRNA nuclear export similarly, suggesting that it is common for cancer-associated SF3B1 mutation to inhibit mRNA nuclear export. Our research highlights the critical role of the THOC5–SF3B1 interaction in the regulation of mRNA nuclear export and provides valuable insights into the impact of SF3B1 mutations on mRNA nuclear export.