SUGP1 loss is the sole driver of SF3B1 hotspot mutant missplicing in cancer.

ABSTRACT: SF3B1 is the most frequently mutated splicing factor in cancer. Mechanistically, such mutations cause missplicing by promoting aberrant 3' splice site usage; however, how this occurs remains controversial. To address this issue, we employed a computational screen of 600 splicing-related proteins to identify those whose reduced expression recapitulated mutant SF3B1 splicing dysregulation. Strikingly, our analysis revealed only two proteins whose loss reproduced this effect. Extending our previous findings, loss of the G-patch protein SUGP1 recapitulated almost all splicing defects induced by SF3B1 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduced ~40% of these defects. However, we found that AQR knockdown caused significant SUGP1 missplicing a

SUBMITTER: Xing P 

PROVIDER: S-EPMC11870612 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature