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Updated: Dec 23, 2025
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Published on: November 5, 2019
Pan-cancer analysis identifies mutations in SUGP1 that recapitulate mutant SF3B1 splicing dysregulation
Zhaoqi Liu1,2,3, Jian Zhang4, Yiwei Sun1,3
1Program for Mathematical Genomics, Columbia University, New York, NY 10032.
Abstract:
The gene encoding the core spliceosomal protein SF3B1 is the most frequently mutated gene encoding a splicing factor in a variety of hematologic malignancies and solid tumors. SF3B1 mutations induce use of cryptic 3' splice sites (3'ss), and these splicing errors contribute to tumorigenesis. However, it is unclear how widespread this type of cryptic 3'ss usage is in cancers and what is the full spectrum of genetic mutations that cause such missplicing. To address this issue, we performed an unbiased pan-cancer analysis to identify genetic alterations that lead to the same aberrant splicing as observed with SF3B1 mutations. This analysis identified multiple mutations in another spliceosomal gene, SUGP1, that correlated with significant usage of cryptic 3'ss known to be utilized in mutant SF3B1 expressing cells. Remarkably, this is consistent with recent biochemical studies that identified a defective interaction between mutant SF3B1 and SUGP1 as the molecular defect responsible for cryptic 3'ss usage. Experimental validation revealed that five different SUGP1 mutations completely or partially recapitulated the 3'ss defects. Our analysis suggests that SUGP1 mutations in cancers can induce missplicing identical or similar to that observed in mutant SF3B1 cancers.
Insights
Mutations in the splicing factor gene SUGP1 can cause cryptic 3' splice site usage, similar to SF3B1 mutations, contributing to cancer development. This study identifies SUGP1 as a key player in cancer-related splicing errors.
Area of Science:
- Molecular Biology
- Cancer Genetics
- RNA Splicing
Background:
- The SF3B1 gene, encoding a core spliceosomal protein, is frequently mutated in cancers.
- SF3B1 mutations lead to aberrant splicing by inducing cryptic 3' splice site (3'ss) usage, contributing to tumorigenesis.
- The full spectrum of genetic mutations causing such missplicing remains largely unknown.
Purpose of the Study:
- To conduct an unbiased pan-cancer analysis to identify genetic alterations causing cryptic 3'ss usage similar to SF3B1 mutations.
- To investigate the role of the spliceosomal gene SUGP1 in cancer-associated aberrant splicing.
Main Methods:
- Unbiased pan-cancer analysis of genetic alterations.
- Correlation analysis between genetic mutations and cryptic 3'ss usage.
- Experimental validation of identified SUGP1 mutations.
Main Results:
- Multiple SUGP1 mutations were identified that correlated with significant usage of cryptic 3'ss.
- These SUGP1 mutations recapitulated splicing defects observed in SF3B1 mutant cells.
- Biochemical studies support a defective interaction between mutant SF3B1 and SUGP1.
Conclusions:
- SUGP1 mutations can induce missplicing identical or similar to that observed in SF3B1 mutant cancers.
- SUGP1 is implicated as a significant contributor to aberrant splicing in various cancers.
- This finding expands the understanding of genetic drivers of cancer-related splicing defects.
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