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<p>Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using <i>Caenorhabditis elegans</i>, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5′-tRH-Gln and 5′-tRH-Asp, from tRNAs. Among them, 5′-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction. Generation of 5′-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1/NRF transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5′-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.</p>

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Ribonuclease DIS3 delays aging and senescence by generating tRNA halves

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Seokjun G. Ha,
  • Hanseul Lee,
  • Jisoo Park,
  • Donghun Lee,
  • Gee-Yoon Lee,
  • Seokjin Ham,
  • Sujeong Kwon,
  • Sangsoon Park,
  • Sieun S. Kim,
  • Yoonji Jung,
  • Jongsun Lee,
  • Jooyeon Sohn,
  • Seon Woo A. An,
  • Heehwa G. Son,
  • Wooseon Hwang,
  • Hyeong-In Kim,
  • Eunseok Kang,
  • Yoon Ki Kim,
  • Gwangrog Lee,
  • Seung-Jae V. Lee

摘要

Transfer RNA (tRNA) halves (tRHs) are generated via the cleavage of tRNAs, but their roles in aging and longevity remain poorly understood. Here, we demonstrate a direct role of tRHs in aging in metazoans. Through a genetic screen using Caenorhabditis elegans, we identify DIS-3/DIS3 as a ribonuclease that catalyzes tRH generation, including 5′-tRH-Gln and 5′-tRH-Asp, from tRNAs. Among them, 5′-tRH-Gln is essential for longevity conferred by various interventions, including dietary restriction. Generation of 5′-tRH-Gln reduces translation via ribosomal protein binding and upregulates the SKN-1/NRF transcription factor responsible for lifespan extension. We further show that mammalian DIS3 contributes to tRH generation and delays cellular senescence through translation downregulation by another tRH, 5′-tRH-Cys. Overall, our data demonstrate that DIS-3/DIS3 is an evolutionarily conserved tRH-generating ribonuclease that counteracts organismal and cellular aging.