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| Status |
Public on Jul 24, 2019 |
| Title |
Cancer-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1 |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is the sole defect of mutant SF3B1 spliceosomes and, since this defect can be rescued, suggests possibilities for therapeutic intervention.
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| Overall design |
15 MDS samples with varying SF3B1 status
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| Contributor(s) |
Ali AM |
| Citation(s) |
31474574, 34930825 |
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| Submission date |
Mar 25, 2019 |
| Last update date |
Feb 02, 2022 |
| Contact name |
Zhaoqi Liu |
| E-mail(s) |
liuzq@big.ac.cn
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| Phone |
6466593600
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| Organization name |
Columbia university
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| Department |
Systems Biology
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| Lab |
The Rabadan Lab
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| Street address |
ICRC Building 8th Floor, Office 803B 1130 St. Nicholas Ave
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| City |
NewYork |
| State/province |
New York |
| ZIP/Postal code |
10032 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (15)
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| Relations |
| BioProject |
PRJNA528926 |
| SRA |
SRP189352 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE128805_RAW.tar |
55.2 Mb |
(http)(custom) |
TAR (of TAB) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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