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A translational program that suppresses metabolism to shield the genome

Author

Listed:
  • Nathan C. Balukoff

    (University of Miami
    University of Miami)

  • J. J. David Ho

    (University of Miami
    University of Miami
    University of Miami)

  • Phaedra R. Theodoridis

    (University of Miami
    University of Miami)

  • Miling Wang

    (University of Miami
    University of Miami)

  • Michael Bokros

    (University of Miami
    University of Miami)

  • Lis M. Llanio

    (University of Miami)

  • Jonathan R. Krieger

    (The Hospital for Sick Children
    Bioinformatics Solutions Inc.)

  • Jonathan H. Schatz

    (University of Miami
    University of Miami)

  • Stephen Lee

    (University of Miami
    University of Miami
    University of Miami)

Abstract

Translatome reprogramming is a primary determinant of protein levels during stimuli adaptation. This raises the question: what are the translatome remodelers that reprogram protein output to activate biochemical adaptations. Here, we identify a translational pathway that represses metabolism to safeguard genome integrity. A system-wide MATRIX survey identified the ancient eIF5A as a pH-regulated translation factor that responds to fermentation-induced acidosis. TMT-pulse-SILAC analysis identified several pH-dependent proteins, including the mTORC1 suppressor Tsc2 and the longevity regulator Sirt1. Sirt1 operates as a pH-sensor that deacetylates nuclear eIF5A during anaerobiosis, enabling the cytoplasmic export of eIF5A/Tsc2 mRNA complexes for translational engagement. Tsc2 induction inhibits mTORC1 to suppress cellular metabolism and prevent acidosis-induced DNA damage. Depletion of eIF5A or Tsc2 leads to metabolic re-initiation and proliferation, but at the expense of incurring substantial DNA damage. We suggest that eIF5A operates as a translatome remodeler that suppresses metabolism to shield the genome.

Suggested Citation

  • Nathan C. Balukoff & J. J. David Ho & Phaedra R. Theodoridis & Miling Wang & Michael Bokros & Lis M. Llanio & Jonathan R. Krieger & Jonathan H. Schatz & Stephen Lee, 2020. "A translational program that suppresses metabolism to shield the genome," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19602-2
    DOI: 10.1038/s41467-020-19602-2
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