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Genetic fusions favor tumorigenesis through degron loss in oncogenes

Author

Listed:
  • Jing Liu

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

  • Collin Tokheim

    (Dana-Farber Cancer Institute
    Harvard T.H. Chan School of Public Health)

  • Jonathan D. Lee

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School
    Paulson School of Engineering and Applied Sciences, Harvard University)

  • Wenjian Gan

    (Medical University of South Carolina)

  • Brian J. North

    (Creighton University)

  • X. Shirley Liu

    (Dana-Farber Cancer Institute
    Harvard T.H. Chan School of Public Health)

  • Pier Paolo Pandolfi

    (Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School
    University of Turin
    Renown Institute for Cancer, Nevada System of Higher Education)

  • Wenyi Wei

    (Beth Israel Deaconess Medical Center, Harvard Medical School)

Abstract

Chromosomal rearrangements can generate genetic fusions composed of two distinct gene sequences, many of which have been implicated in tumorigenesis and progression. Our study proposes a model whereby oncogenic gene fusions frequently alter the protein stability of the resulting fusion products, via exchanging protein degradation signal (degron) between gene sequences. Computational analyses of The Cancer Genome Atlas (TCGA) identify 2,406 cases of degron exchange events and reveal an enrichment of oncogene stabilization due to loss of degrons from fusion. Furthermore, we identify and experimentally validate that some recurrent fusions, such as BCR-ABL, CCDC6-RET and PML-RARA fusions, perturb protein stability by exchanging internal degrons. Likewise, we also validate that EGFR or RAF1 fusions can be stabilized by losing a computationally-predicted C-terminal degron. Thus, complementary to enhanced oncogene transcription via promoter swapping, our model of degron loss illustrates another general mechanism for recurrent fusion proteins in driving tumorigenesis.

Suggested Citation

  • Jing Liu & Collin Tokheim & Jonathan D. Lee & Wenjian Gan & Brian J. North & X. Shirley Liu & Pier Paolo Pandolfi & Wenyi Wei, 2021. "Genetic fusions favor tumorigenesis through degron loss in oncogenes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26871-y
    DOI: 10.1038/s41467-021-26871-y
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    References listed on IDEAS

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