IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26871-y.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26871-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26871-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Oecd, 2018. "Case Law," Nuclear Law Bulletin, OECD Publishing, vol. 2017(1), pages 71-74.
    2. Oecd, 2018. "Case law," Nuclear Law Bulletin, OECD Publishing, vol. 2018(1), pages 84-92.
    3. Alberto C. Vitari & Kevin G. Leong & Kim Newton & Cindy Yee & Karen O’Rourke & Jinfeng Liu & Lilian Phu & Rajesh Vij & Ronald Ferrando & Suzana S. Couto & Sankar Mohan & Ajay Pandita & Jo-Anne Hongo &, 2011. "COP1 is a tumour suppressor that causes degradation of ETS transcription factors," Nature, Nature, vol. 474(7351), pages 403-406, June.
    4. Hiroyuki Inuzuka & Shavali Shaik & Ichiro Onoyama & Daming Gao & Alan Tseng & Richard S. Maser & Bo Zhai & Lixin Wan & Alejandro Gutierrez & Alan W. Lau & Yonghong Xiao & Amanda L. Christie & Jon Aste, 2011. "SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction," Nature, Nature, vol. 471(7336), pages 104-109, March.
    5. Oecd, 2018. "Case law," Nuclear Law Bulletin, OECD Publishing, vol. 2016(2), pages 63-65.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Taek-Chin Cheong & Ahram Jang & Qi Wang & Giulia C. Leonardi & Biagio Ricciuti & Joao V. Alessi & Alessandro Di Federico & Mark M. Awad & Maria K. Lehtinen & Marian H. Harris & Roberto Chiarle, 2024. "Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ian F. Price & Jillian A. Wagner & Benjamin Pastore & Hannah L. Hertz & Wen Tang, 2023. "C. elegans germ granules sculpt both germline and somatic RNAome," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Solip Park & Fran Supek & Ben Lehner, 2021. "Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Hui Chen & Zeyang Wang & Lihai Gong & Qixuan Wang & Wenyan Chen & Jia Wang & Xuelian Ma & Ruofan Ding & Xing Li & Xudong Zou & Mireya Plass & Cheng Lian & Ting Ni & Gong-Hong Wei & Wei Li & Lin Deng &, 2024. "A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Wen-Xiang Liu & Hai-Ning Liu & Zhan-Ping Weng & Qi Geng & Yue Zhang & Ya-Feng Li & Wei Shen & Yang Zhou & Teng Zhang, 2023. "Maternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26871-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.