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

Pre-mRNA splicing and nuclear export are coordinated processes that ensure efficient and accurate gene expression. In recent years, disruptions in this process have been found to result in substantial gene expression aberrations, with potential contributions from SF3B1 mutations, whose mechanism remains elusive. The present study reveals that the K700E mutation in SF3B1 attenuates its interaction with THOC5, resulting in reduced mRNA binding by THOC5, and ultimately, the inhibition of mRNA nuclear export. Interestingly, overexpressing THOC5 can restore the attenuated interaction, facilitating mRNA nuclear export. Importantly, other cancer-associated SF3B1 mutations may exert a similar impact. Our research highlights the critical role of the THOC5–SF3B1 interaction in regulating mRNA nuclear export and provides valuable insights into the impact of SF3B1 mutations on this process. Overall design: Cytoplasmic and nuclear RNA obtained from HEK293T cells transiently transfected with pIRES2-SF3B1 WT (WT) or pIRES2-SF3B1 K700E (K700E).