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DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders

Author

Listed:
  • Ramona Weber

    (Department of Biochemistry, Max Planck Institute for Developmental Biology
    University of Zurich)

  • Leon Kleemann

    (Department of Biochemistry, Max Planck Institute for Developmental Biology
    University of Bern)

  • Insa Hirschberg

    (Friedrich Miescher Laboratory of the Max Planck Society)

  • Min-Yi Chung

    (Department of Biochemistry, Max Planck Institute for Developmental Biology)

  • Eugene Valkov

    (Department of Biochemistry, Max Planck Institute for Developmental Biology
    Center for Cancer Research, National Cancer Institute)

  • Cátia Igreja

    (Department of Biochemistry, Max Planck Institute for Developmental Biology
    Department for Integrative Evolutionary Biology, Max Planck Institute for Biology)

Abstract

Half of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here, we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is required for translation initiation on select transcripts. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-mediated translation occurs on messenger RNAs (mRNAs) with long, structure-prone 5′ leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates main CDS, but not uORF, translation suggesting a role for DAP5 in translation re-initiation. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35019-5
    DOI: 10.1038/s41467-022-35019-5
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    1. 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.
    2. Shintaro Iwasaki & Stephen N. Floor & Nicholas T. Ingolia, 2016. "Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor," Nature, Nature, vol. 534(7608), pages 558-561, June.
    3. 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.
    4. Alan Brown & Sichen Shao & Jason Murray & Ramanujan S. Hegde & V. Ramakrishnan, 2015. "Structural basis for stop codon recognition in eukaryotes," Nature, Nature, vol. 524(7566), pages 493-496, August.
    5. 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.
    6. Ataman Sendoel & Joshua G. Dunn & Edwin H. Rodriguez & Shruti Naik & Nicholas C. Gomez & Brian Hurwitz & John Levorse & Brian D. Dill & Daniel Schramek & Henrik Molina & Jonathan S. Weissman & Elaine , 2017. "Translation from unconventional 5′ start sites drives tumour initiation," Nature, Nature, vol. 541(7638), pages 494-499, January.
    7. Kotaro Fujii & Zhen Shi & Olena Zhulyn & Nicolas Denans & Maria Barna, 2017. "Pervasive translational regulation of the cell signalling circuitry underlies mammalian development," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    8. Columba Parra & Amanda Ernlund & Amandine Alard & Kelly Ruggles & Beatrix Ueberheide & Robert J. Schneider, 2018. "A widespread alternate form of cap-dependent mRNA translation initiation," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
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