IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-18452-2.html
   My bibliography  Save this article

DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4

Author

Listed:
  • Jonathan Bohlen

    (German Cancer Research Center (DKFZ)
    CellNetworks—Cluster of Excellence, Heidelberg University
    Heidelberg University
    Heidelberg Biosciences International Graduate School (HBIGS))

  • Liza Harbrecht

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Saioa Blanco

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    National Center for Tumor Diseases (NCT), partner site)

  • Katharina Clemm von Hohenberg

    (German Cancer Research Center (DKFZ)
    CellNetworks—Cluster of Excellence, Heidelberg University
    Heidelberg University
    National Center for Tumor Diseases (NCT), partner site)

  • Kai Fenzl

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    Heidelberg Biosciences International Graduate School (HBIGS)
    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance)

  • Günter Kramer

    (German Cancer Research Center (DKFZ)
    National Center for Tumor Diseases (NCT), partner site
    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance)

  • Bernd Bukau

    (German Cancer Research Center (DKFZ)
    National Center for Tumor Diseases (NCT), partner site
    Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance)

  • Aurelio A. Teleman

    (German Cancer Research Center (DKFZ)
    CellNetworks—Cluster of Excellence, Heidelberg University
    Heidelberg University
    Heidelberg Biosciences International Graduate School (HBIGS))

Abstract

Translation efficiency varies considerably between different mRNAs, thereby impacting protein expression. Translation of the stress response master-regulator ATF4 increases upon stress, but the molecular mechanisms are not well understood. We discover here that translation factors DENR, MCTS1 and eIF2D are required to induce ATF4 translation upon stress by promoting translation reinitiation in the ATF4 5′UTR. We find DENR and MCTS1 are only needed for reinitiation after upstream Open Reading Frames (uORFs) containing certain penultimate codons, perhaps because DENR•MCTS1 are needed to evict only certain tRNAs from post-termination 40S ribosomes. This provides a model for how DENR and MCTS1 promote translation reinitiation. Cancer cells, which are exposed to many stresses, require ATF4 for survival and proliferation. We find a strong correlation between DENR•MCTS1 expression and ATF4 activity across cancers. Furthermore, additional oncogenes including a-Raf, c-Raf and Cdk4 have long uORFs and are translated in a DENR•MCTS1 dependent manner.

Suggested Citation

  • Jonathan Bohlen & Liza Harbrecht & Saioa Blanco & Katharina Clemm von Hohenberg & Kai Fenzl & Günter Kramer & Bernd Bukau & Aurelio A. Teleman, 2020. "DENR promotes translation reinitiation via ribosome recycling to drive expression of oncogenes including ATF4," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18452-2
    DOI: 10.1038/s41467-020-18452-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-18452-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-18452-2?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
    ---><---

    Citations

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


    Cited by:

    1. Yu H. Sun & Ruoqiao Huiyi Wang & Khai Du & Jiang Zhu & Jihong Zheng & Li Huitong Xie & Amanda A. Pereira & Chao Zhang & Emiliano P. Ricci & Xin Zhiguo Li, 2021. "Coupled protein synthesis and ribosome-guided piRNA processing on mRNAs," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    2. Ramona Weber & Leon Kleemann & Insa Hirschberg & Min-Yi Chung & Eugene Valkov & Cátia Igreja, 2022. "DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Katharina Clemm von Hohenberg & Sandra Müller & Sibylle Schleich & Matthias Meister & Jonathan Bohlen & Thomas G. Hofmann & Aurelio A. Teleman, 2022. "Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Baiwen Chen & Jiajia Hu & Xianting Hu & Huifang Chen & Rujuan Bao & Yatao Zhou & Youqiong Ye & Meixiao Zhan & Wei Cai & Huabin Li & Hua-Bing Li, 2022. "DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion," Nature Communications, Nature, vol. 13(1), pages 1-14, 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:11:y:2020:i:1:d:10.1038_s41467-020-18452-2. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.