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In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress

Author

Listed:
  • Noah Peña

    (University of Chicago)

  • Yichen Hou

    (University of Chicago)

  • Christopher P. Watkins

    (University of Chicago)

  • Sihao Huang

    (University of Chicago)

  • Wen Zhang

    (University of Chicago)

  • Christopher D. Katanski

    (University of Chicago)

  • Tao Pan

    (University of Chicago
    University of Chicago)

Abstract

Transfer RNA (tRNA) is the most abundant cellular RNA family in terms of copy numbers. It not only folds into defined structures but also has complex cellular interaction networks involving aminoacyl-tRNA synthetases, translation factors, and ribosomes. The human tRNAome is comprised of chromosomal-encoded tRNAs with a large sequence diversity and mitochondrial-encoded tRNAs with A/U-rich sequences and noncanonical tertiary interactions. How tRNA folding and interactions in a eukaryotic cell respond to stress is poorly understood. Here, we develop DM-DMS-MaPseq, which utilizes in vivo dimethyl-sulfate (DMS) chemical probing and mutational profiling (MaP) coupled with demethylase (DM) treatment in transcriptome-wide tRNA sequencing to profile structures and the cellular interactions of human chromosomal and mitochondrial-encoded tRNAs. We found that tRNAs maintain stable structures in vivo, but the in vivo DMS profiles are vastly different from those in vitro, which can be explained by their interactions with cellular proteins and the ribosome. We also identify cytosolic and mitochondrial tRNA structure and interaction changes upon arsenite treatment, a type of oxidative stress that induces translational reprogramming, which is consistent with global translation repression in both compartments. Our results reveal variations of tRNA structurome and dynamic interactome that have functional consequences in translational regulation.

Suggested Citation

  • Noah Peña & Yichen Hou & Christopher P. Watkins & Sihao Huang & Wen Zhang & Christopher D. Katanski & Tao Pan, 2025. "In vivo structure profiling reveals human cytosolic and mitochondrial tRNA structurome and interactome in response to stress," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59435-5
    DOI: 10.1038/s41467-025-59435-5
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    as
    1. Robert C. Spitale & Ryan A. Flynn & Qiangfeng Cliff Zhang & Pete Crisalli & Byron Lee & Jong-Wha Jung & Hannes Y. Kuchelmeister & Pedro J. Batista & Eduardo A. Torre & Eric T. Kool & Howard Y. Chang, 2015. "Erratum: Structural imprints in vivo decode RNA regulatory mechanisms," Nature, Nature, vol. 527(7577), pages 264-264, November.
    2. Jiazhi Li & Longfei Wang & Quentin Hahn & Radosław P. Nowak & Thibault Viennet & Esteban A. Orellana & Shourya S. Roy Burman & Hong Yue & Moritz Hunkeler & Pietro Fontana & Hao Wu & Haribabu Arthanari, 2023. "Structural basis of regulated m7G tRNA modification by METTL1–WDR4," Nature, Nature, vol. 613(7943), pages 391-397, January.
    3. Michael Kertesz & Yue Wan & Elad Mazor & John L. Rinn & Robert C. Nutter & Howard Y. Chang & Eran Segal, 2010. "Genome-wide measurement of RNA secondary structure in yeast," Nature, Nature, vol. 467(7311), pages 103-107, September.
    4. Wade Winkler & Ali Nahvi & Ronald R. Breaker, 2002. "Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression," Nature, Nature, vol. 419(6910), pages 952-956, October.
    5. Takeo Suzuki & Yuka Yashiro & Ittoku Kikuchi & Yuma Ishigami & Hironori Saito & Ikuya Matsuzawa & Shunpei Okada & Mari Mito & Shintaro Iwasaki & Ding Ma & Xuewei Zhao & Kana Asano & Huan Lin & Yohei K, 2020. "Complete chemical structures of human mitochondrial tRNAs," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    6. Mikael Holm & S. Kundhavai Natchiar & Emily J. Rundlet & Alexander G. Myasnikov & Zoe L. Watson & Roger B. Altman & Hao-Yuan Wang & Jack Taunton & Scott C. Blanchard, 2023. "mRNA decoding in human is kinetically and structurally distinct from bacteria," Nature, Nature, vol. 617(7959), pages 200-207, May.
    7. Qing-Jun Luo & Jinsong Zhang & Pan Li & Qing Wang & Yue Zhang & Biswajoy Roy-Chaudhuri & Jianpeng Xu & Mark A. Kay & Qiangfeng Cliff Zhang, 2021. "RNA structure probing reveals the structural basis of Dicer binding and cleavage," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    8. Tomas Adomavicius & Margherita Guaita & Yu Zhou & Martin D. Jennings & Zakia Latif & Alan M. Roseman & Graham D. Pavitt, 2019. "The structural basis of translational control by eIF2 phosphorylation," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    9. Heena Khatter & Alexander G. Myasnikov & S. Kundhavai Natchiar & Bruno P. Klaholz, 2015. "Structure of the human 80S ribosome," Nature, Nature, vol. 520(7549), pages 640-645, April.
    10. Christopher P. Watkins & Wen Zhang & Adam C. Wylder & Christopher D. Katanski & Tao Pan, 2022. "A multiplex platform for small RNA sequencing elucidates multifaceted tRNA stress response and translational regulation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    11. Robert C. Spitale & Ryan A. Flynn & Qiangfeng Cliff Zhang & Pete Crisalli & Byron Lee & Jong-Wha Jung & Hannes Y. Kuchelmeister & Pedro J. Batista & Eduardo A. Torre & Eric T. Kool & Howard Y. Chang, 2015. "Structural imprints in vivo decode RNA regulatory mechanisms," Nature, Nature, vol. 519(7544), pages 486-490, March.
    12. Silvi Rouskin & Meghan Zubradt & Stefan Washietl & Manolis Kellis & Jonathan S. Weissman, 2014. "Genome-wide probing of RNA structure reveals active unfolding of mRNA structures in vivo," Nature, Nature, vol. 505(7485), pages 701-705, January.
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