SUGP1 Loss is the Sole Driver of SF3B1 Hotspot Mutant Missplicing in Cancer

Overview

Journal bioRxiv

Date 2025 Mar 3

PMID 40027711

Authors

Peiqi Xing

Pedro Bak-Gordon

Jindou Xie

Jian Zhang

Zhaoqi Liu

James L Manley

Affiliations

Soon will be listed here.

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 hotspot mutations. Unexpectedly, loss of the RNA helicase Aquarius (AQR) reproduced ~40% of these defects. However, we found that AQR knockdown caused significant missplicing and reduced protein levels, suggesting that AQR loss reproduced mutant SF3B1 splicing defects only indirectly. This study advances our understanding of missplicing caused by oncogenic mutations, and highlights the fundamental role of SUGP1 in this process.

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