Cancer-associated SF3B1 mutations inhibit mRNA nuclear export by disrupting SF3B1-THOC5 interactions

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Mutations in SF3B1 are prevalent in numerous cancers, driving progression via altered RNA splicing.
• Defective mRNA nuclear export was observed in cells with the SF3B1 K700E mutation, but the underlying mechanism was unknown.

Purpose of the Study:

• To elucidate the mechanism by which SF3B1 mutations impair mRNA nuclear export.
• To investigate the role of the THO complex component THOC5 in this process.

Main Methods:

• Investigated the interaction between SF3B1 and THOC5 in cells with the SF3B1 K700E mutation.
• Assessed mRNA binding and nuclear export efficiency of specific mRNAs.
• Examined the effect of THOC5 overexpression on mRNA export.

Main Results:

• The SF3B1 K700E mutation weakens its interaction with THOC5, a key part of the mRNA nuclear export machinery.
• This impaired interaction led to reduced THOC5 binding to certain mRNAs and inhibited their nuclear export.
• Overexpressing THOC5 rescued the nuclear export defect in SF3B1 K700E mutant cells.
• Other cancer-associated SF3B1 mutations also impaired mRNA nuclear export.

Conclusions:

• The interaction between THOC5 and SF3B1 is crucial for regulating mRNA nuclear export.
• Cancer-associated SF3B1 mutations commonly disrupt mRNA nuclear export, potentially contributing to tumorigenesis.
• Targeting the SF3B1-THOC5 pathway may offer therapeutic strategies for SF3B1-mutated cancers.