Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1.
Mol Cell
; 76(1): 82-95.e7, 2019 10 03.
Article
em En
| MEDLINE
| ID: mdl-31474574
ABSTRACT
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 suggest 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 a common defect of spliceosomes with disease-causing SF3B1 mutations and, because this defect can be rescued, suggests possibilities for therapeutic intervention.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Síndromes Mielodisplásicas
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Leucemia Eritroblástica Aguda
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Splicing de RNA
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Spliceossomos
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Fatores de Processamento de RNA
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Mutação
Limite:
Humans
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos