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Cyclin B/CDK1 and Cyclin A/CDK2 phosphorylate DENR to promote mitotic protein translation and faithful cell division

Author

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  • Katharina Clemm von Hohenberg

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    CellNetworks—Cluster of Excellence, Heidelberg University
    Universitätsmedizin Mannheim)

  • Sandra Müller

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Sibylle Schleich

    (German Cancer Research Center (DKFZ)
    Heidelberg University)

  • Matthias Meister

    (German Cancer Research Center (DKFZ))

  • Jonathan Bohlen

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    CellNetworks—Cluster of Excellence, Heidelberg University
    Laboratory of Human Genetics of Infectious Diseases, Necker Branch)

  • Thomas G. Hofmann

    (University Medical Center Mainz at the Johannes Gutenberg University of Mainz)

  • Aurelio A. Teleman

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    CellNetworks—Cluster of Excellence, Heidelberg University)

Abstract

DENR and MCTS1 have been identified as oncogenes in several different tumor entities. The heterodimeric DENR·MCTS1 protein complex promotes translation of mRNAs containing upstream Open Reading Frames (uORFs). We show here that DENR is phosphorylated on Serine 73 by Cyclin B/CDK1 and Cyclin A/CDK2 at the onset of mitosis, and then dephosphorylated as cells exit mitosis. Phosphorylation of Ser73 promotes mitotic stability of DENR protein and prevents its cleavage at Asp26. This leads to enhanced translation of mRNAs involved in mitosis. Indeed, we find that roughly 40% of all mRNAs with elevated translation in mitosis are DENR targets. In the absence of DENR or of Ser73 phosphorylation, cells display elevated levels of aberrant mitoses and cell death. This provides a mechanism how the cell cycle regulates translation of a subset of mitotically relevant mRNAs during mitosis.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28265-0
    DOI: 10.1038/s41467-022-28265-0
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    1. Björn Schwanhäusser & Dorothea Busse & Na Li & Gunnar Dittmar & Johannes Schuchhardt & Jana Wolf & Wei Chen & Matthias Selbach, 2011. "Global quantification of mammalian gene expression control," Nature, Nature, vol. 473(7347), pages 337-342, May.
    2. Deepika Vasudevan & Sarah D. Neuman & Amy Yang & Lea Lough & Brian Brown & Arash Bashirullah & Timothy Cardozo & Hyung Don Ryoo, 2020. "Translational induction of ATF4 during integrated stress response requires noncanonical initiation factors eIF2D and DENR," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. 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.
    4. Sibylle Schleich & Katrin Strassburger & Philipp Christoph Janiesch & Tatyana Koledachkina & Katharine K. Miller & Katharina Haneke & Yong-Sheng Cheng & Katrin Küchler & Georg Stoecklin & Kent E. Dunc, 2014. "DENR–MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth," Nature, Nature, vol. 512(7513), pages 208-212, August.
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