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Spt4 drives cellular senescence by activating non-coding RNA transcription in ribosomal RNA gene clusters

Masaaki Yokoyama, Mariko Sasaki, View ORCID ProfileTakehiko Kobayashi
doi: https://doi.org/10.1101/2022.04.22.488906
Masaaki Yokoyama
1Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
2Department of Biological Sciences, Graduate School of Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
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Mariko Sasaki
1Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
2Department of Biological Sciences, Graduate School of Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
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  • For correspondence: sasakim@iqb.u-tokyo.ac.jp tako2015@iqb.u-tokyo.ac.jp
Takehiko Kobayashi
1Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
2Department of Biological Sciences, Graduate School of Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
3Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, JAPAN
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  • ORCID record for Takehiko Kobayashi
  • For correspondence: sasakim@iqb.u-tokyo.ac.jp tako2015@iqb.u-tokyo.ac.jp
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SUMMARY

Genome instability can drive aging in many organisms. The ribosomal RNA gene (rDNA) cluster is one of the most unstable regions in the genome. Replicative lifespan in budding yeast is correlated to rDNA stability, suggesting that the rDNA locus produces an aging signal. To understand the underlying mechanism, we looked for yeast mutants with more stable rDNA and longer lifespan than wild-type cells. We reveal that absence of a transcription elongation factor, Spt4, resulted in an increased rDNA stability, a reduced activity of the regulatory E-pro promoter in the rDNA, and extended replicative lifespan in a SIR2-dependent manner. Spt4-dependent lifespan restriction was abolished in the absence of non-coding RNA transcription at the E-pro locus. The amount of Spt4 increases and its function becomes more important as cells age. These findings suggest that Spt4 is a promising aging factor that accelerates cellular senescence through rDNA instability driven by non-coding RNA transcription

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 22, 2022.
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Spt4 drives cellular senescence by activating non-coding RNA transcription in ribosomal RNA gene clusters
Masaaki Yokoyama, Mariko Sasaki, Takehiko Kobayashi
bioRxiv 2022.04.22.488906; doi: https://doi.org/10.1101/2022.04.22.488906
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Spt4 drives cellular senescence by activating non-coding RNA transcription in ribosomal RNA gene clusters
Masaaki Yokoyama, Mariko Sasaki, Takehiko Kobayashi
bioRxiv 2022.04.22.488906; doi: https://doi.org/10.1101/2022.04.22.488906

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