SUGP1 loss drives SF3B1 hotspot mutant missplicing in cancer

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• The splicing factor SF3B1 is frequently mutated in cancer, leading to aberrant 3' splice site usage and missplicing.
• The precise molecular mechanisms underlying SF3B1 mutation-induced splicing dysregulation remain incompletely understood.

Purpose of the Study:

• To computationally identify proteins whose reduced expression phenocopies splicing defects caused by oncogenic SF3B1 mutations.
• To elucidate the mechanistic link between SF3B1 mutations and splicing alterations.

Main Methods:

• A computational screen of 600 splicing-related proteins was performed.
• Knockdown and knockout strategies were used to assess the functional impact of protein loss on splicing.
• Comparison of splicing defects induced by SF3B1 mutations with those caused by the loss of other splicing factors.

Main Results:

• The study identified two proteins whose loss recapitulates SF3B1 mutation-associated splicing defects.
• Loss of the G-patch protein SUGP1 phenocopied nearly all splicing defects observed with SF3B1 hotspot mutations.
• Loss of the RNA helicase Aquarius (AQR) reproduced approximately 40% of these defects, but indirectly through SUGP1 missplicing.

Conclusions:

• SUGP1 plays a fundamental and direct role in mediating splicing defects caused by oncogenic SF3B1 mutations.
• AQR contributes indirectly to SF3B1-associated splicing defects, primarily by influencing SUGP1 levels and splicing.
• This research deepens the understanding of cancer-related missplicing and identifies key regulatory players.