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Pervasive downstream RNA hairpins dynamically dictate start-codon selection

Author

Listed:
  • Yezi Xiang

    (Duke University
    Duke University)

  • Wenze Huang

    (Tsinghua University
    Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Lianmei Tan

    (Duke University)

  • Tianyuan Chen

    (Duke University
    Duke University)

  • Yang He

    (Duke University
    Duke University)

  • Patrick S. Irving

    (University of North Carolina)

  • Kevin M. Weeks

    (University of North Carolina)

  • Qiangfeng Cliff Zhang

    (Tsinghua University
    Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Xinnian Dong

    (Duke University
    Duke University)

Abstract

Translational reprogramming allows organisms to adapt to changing conditions. Upstream start codons (uAUGs), which are prevalently present in mRNAs, have crucial roles in regulating translation by providing alternative translation start sites1–4. However, what determines this selective initiation of translation between conditions remains unclear. Here, by integrating transcriptome-wide translational and structural analyses during pattern-triggered immunity in Arabidopsis, we found that transcripts with immune-induced translation are enriched with upstream open reading frames (uORFs). Without infection, these uORFs are selectively translated owing to hairpins immediately downstream of uAUGs, presumably by slowing and engaging the scanning preinitiation complex. Modelling using deep learning provides unbiased support for these recognizable double-stranded RNA structures downstream of uAUGs (which we term uAUG-ds) being responsible for the selective translation of uAUGs, and allows the prediction and rational design of translating uAUG-ds. We found that uAUG-ds-mediated regulation can be generalized to human cells. Moreover, uAUG-ds-mediated start-codon selection is dynamically regulated. After immune challenge in plants, induced RNA helicases that are homologous to Ded1p in yeast and DDX3X in humans resolve these structures, allowing ribosomes to bypass uAUGs to translate downstream defence proteins. This study shows that mRNA structures dynamically regulate start-codon selection. The prevalence of this RNA structural feature and the conservation of RNA helicases across kingdoms suggest that mRNA structural remodelling is a general feature of translational reprogramming.

Suggested Citation

  • Yezi Xiang & Wenze Huang & Lianmei Tan & Tianyuan Chen & Yang He & Patrick S. Irving & Kevin M. Weeks & Qiangfeng Cliff Zhang & Xinnian Dong, 2023. "Pervasive downstream RNA hairpins dynamically dictate start-codon selection," Nature, Nature, vol. 621(7978), pages 423-430, September.
  • Handle: RePEc:nat:nature:v:621:y:2023:i:7978:d:10.1038_s41586-023-06500-y
    DOI: 10.1038/s41586-023-06500-y
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    Cited by:

    1. Runlai Hang & Hao Li & Wenjing Liu & Runyu Wang & Hao Hu & Meng Chen & Chenjiang You & Xuemei Chen, 2024. "HOT3/eIF5B1 confers Kozak motif-dependent translational control of photosynthesis-associated nuclear genes for chloroplast biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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