Characterization of the SF3B1-SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing

Area of Science:

• Molecular biology
• Cancer genetics
• Protein interactions

Background:

• The spliceosomal gene SF3B1 is frequently mutated in various cancers.
• SF3B1 hotspot mutations are known to cause loss of splicing factor SUGP1 from spliceosomes.
• The specific molecular interactions between SF3B1 and SUGP1 in cancer are not well understood.

Purpose of the Study:

• To structurally and experimentally characterize the interaction between SF3B1 and SUGP1.
• To elucidate the impact of cancer-associated SF3B1 mutations on this interaction.
• To understand the role of the SF3B1-SUGP1 complex in spliceosome function.

Main Methods:

• Structural modeling to predict protein-protein interactions.
• Experimental validation of predicted interactions and mutation effects.
• Analysis of splicing alterations caused by SF3B1 mutations.

Main Results:

• Structural modeling identified key contact regions between SF3B1 and SUGP1.
• Cancer-associated mutations in SF3B1 weaken or disrupt the SF3B1-SUGP1 interaction.
• Disruption of the SF3B1-SUGP1 interaction alters splicing patterns, mimicking SF3B1 cancer mutations.
• The SF3B1-SUGP1 interaction facilitates the interaction of SUGP1 with the helicase DHX15.

Conclusions:

• The study provides a molecular understanding of the SF3B1-SUGP1 interaction crucial for splicing.
• Cancer-associated mutations frequently disrupt this critical interaction.
• This disruption impacts splicing fidelity and contributes to oncogenesis.