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Disease-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1.

Mol Cell. 2019 Oct 03;76(1):82-95.e7. Epub 2019 Aug 29
Jian Zhang 1 , Abdullah M Ali 2 , Yen K Lieu 3 , Zhaoqi Liu 4 , Jianchao Gao 1 , Raul Rabadan 4 , Azra Raza 5 , Siddhartha Mukherjee 6 , James L Manley 7
Jian Zhang 1 , Abdullah M Ali 2 , Yen K Lieu 3 , Zhaoqi Liu 4 , Jianchao Gao 1 , Raul Rabadan 4 , Azra Raza 5 , Siddhartha Mukherjee 6 , James L Manley 7
+ et al

[No authors listed]

Author information
  • 1 Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • 2 Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
  • 3 Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.
  • 4 Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA.
  • 5 Irving Cancer Research Center, Columbia University, New York, NY 10032, USA; Division of Hematology/Oncology, Department of Medicine, Columbia University, New York, NY 10032, USA.
  • 6 Irving Cancer Research Center, Columbia University, New York, NY 10032, USA; Division of Hematology/Oncology, Department of Medicine, Columbia University, New York, NY 10032, USA. Electronic address: sm3252@cumc.columbia.edu.
  • 7 Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: jlm2@columbia.edu.

摘要

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.

KEYWORDS: SF1, SRSF2, U2 snRNP, U2AF1, U2AF2, branch point, leukemia, myelodysplastic syndromes, p14, spliceosome

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