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Spliceosomal disruption of the non-canonical BAF complex in cancer

Author

Listed:
  • Daichi Inoue

    (Memorial Sloan Kettering Cancer Center
    Foundation for Biomedical Research and Innovation at Kobe)

  • Guo-Liang Chew

    (Fred Hutchinson Cancer Research Center
    Fred Hutchinson Cancer Research Center)

  • Bo Liu

    (Memorial Sloan Kettering Cancer Center)

  • Brittany C. Michel

    (Dana-Farber Cancer Institute
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Joseph Pangallo

    (Fred Hutchinson Cancer Research Center
    Fred Hutchinson Cancer Research Center)

  • Andrew R. D’Avino

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Tyler Hitchman

    (Memorial Sloan Kettering Cancer Center)

  • Khrystyna North

    (Fred Hutchinson Cancer Research Center
    Fred Hutchinson Cancer Research Center
    University of Washington)

  • Stanley Chun-Wei Lee

    (Memorial Sloan Kettering Cancer Center)

  • Lillian Bitner

    (Memorial Sloan Kettering Cancer Center)

  • Ariele Block

    (Memorial Sloan Kettering Cancer Center)

  • Amanda R. Moore

    (Memorial Sloan Kettering Cancer Center)

  • Akihide Yoshimi

    (Memorial Sloan Kettering Cancer Center)

  • Luisa Escobar-Hoyos

    (Memorial Sloan Kettering Cancer Center)

  • Hana Cho

    (Memorial Sloan Kettering Cancer Center)

  • Alex Penson

    (Memorial Sloan Kettering Cancer Center)

  • Sydney X. Lu

    (Memorial Sloan Kettering Cancer Center)

  • Justin Taylor

    (Memorial Sloan Kettering Cancer Center)

  • Yu Chen

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Cigall Kadoch

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Omar Abdel-Wahab

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Robert K. Bradley

    (Fred Hutchinson Cancer Research Center
    Fred Hutchinson Cancer Research Center
    University of Washington)

Abstract

SF3B1 is the most commonly mutated RNA splicing factor in cancer1–4, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L5–7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.

Suggested Citation

  • Daichi Inoue & Guo-Liang Chew & Bo Liu & Brittany C. Michel & Joseph Pangallo & Andrew R. D’Avino & Tyler Hitchman & Khrystyna North & Stanley Chun-Wei Lee & Lillian Bitner & Ariele Block & Amanda R. , 2019. "Spliceosomal disruption of the non-canonical BAF complex in cancer," Nature, Nature, vol. 574(7778), pages 432-436, October.
  • Handle: RePEc:nat:nature:v:574:y:2019:i:7778:d:10.1038_s41586-019-1646-9
    DOI: 10.1038/s41586-019-1646-9
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    Cited by:

    1. Sophie A. Herbst & Mattias Vesterlund & Alexander J. Helmboldt & Rozbeh Jafari & Ioannis Siavelis & Matthias Stahl & Eva C. Schitter & Nora Liebers & Berit J. Brinkmann & Felix Czernilofsky & Tobias R, 2022. "Proteogenomics refines the molecular classification of chronic lymphocytic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Zixiang Wang & Shourong Wang & Junchao Qin & Xiyu Zhang & Gang Lu & Hongbin Liu & Haiyang Guo & Ligang Wu & Victoria O. Shender & Changshun Shao & Beihua Kong & Zhaojian Liu, 2022. "Splicing factor BUD31 promotes ovarian cancer progression through sustaining the expression of anti-apoptotic BCL2L12," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Caroline Gubser Keller & Youngah Shin & Alex Mas Monteys & Nicole Renaud & Martin Beibel & Natalia Teider & Thomas Peters & Thomas Faller & Sophie St-Cyr & Judith Knehr & Guglielmo Roma & Alejandro Re, 2022. "An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Muran Xiao & Shinji Kondo & Masaki Nomura & Shinichiro Kato & Koutarou Nishimura & Weijia Zang & Yifan Zhang & Tomohiro Akashi & Aaron Viny & Tsukasa Shigehiro & Tomokatsu Ikawa & Hiromi Yamazaki & Mi, 2023. "BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. Jonathan P. Ling & Alexei M. Bygrave & Clayton P. Santiago & Rogger P. Carmen-Orozco & Vickie T. Trinh & Minzhong Yu & Yini Li & Ying Liu & Kyra D. Bowden & Leighton H. Duncan & Jeong Han & Kamil Tane, 2022. "Cell-specific regulation of gene expression using splicing-dependent frameshifting," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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