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

Masaaki Yokoyama; Mariko Sasaki; Takehiko Kobayashi

doi:10.1016/j.celrep.2022.111944

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

Cell Rep. 2023 Jan 31;42(1):111944. doi: 10.1016/j.celrep.2022.111944. Epub 2023 Jan 10.

Authors

Masaaki Yokoyama¹, Mariko Sasaki², Takehiko Kobayashi³

Affiliations

¹ Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
² Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: sasakim@iqb.u-tokyo.ac.jp.
³ Laboratory of Genome Regeneration, Institute for Quantitative Biosciences (IQB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: tako2015@iqb.u-tokyo.ac.jp.

PMID: 36640349
DOI: 10.1016/j.celrep.2022.111944

Abstract

Genome instability can drive aging in many organisms. The ribosomal RNA gene (rDNA) cluster is one of the most unstable regions in the genome and the stability of this region impacts replicative lifespan in budding yeast. To understand the underlying mechanism, we search for yeast mutants with stabler rDNA and longer lifespans than wild-type cells. We show that absence of a transcription elongation factor, Spt4, results in increased rDNA stability, reduced levels of non-coding RNA transcripts from the regulatory E-pro promoter in the rDNA, and extended replicative lifespan in a SIR2-dependent manner. Spt4-dependent lifespan restriction is 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.

Keywords: CP: Cell biology; CP: Molecular biology; Spt4; budding yeast; genome instability; lifespan; non-coding RNA transcription; rDNA; senescence.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cellular Senescence* / genetics
DNA, Ribosomal / genetics
Genes, rRNA / genetics
Nuclear Proteins / metabolism
RNA, Untranslated / genetics
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism
Saccharomyces cerevisiae Proteins* / genetics
Saccharomyces cerevisiae Proteins* / metabolism
Transcription, Genetic
Transcriptional Elongation Factors / genetics

Substances

DNA, Ribosomal
Saccharomyces cerevisiae Proteins
RNA, Untranslated
SPT4 protein, S cerevisiae
Nuclear Proteins
Transcriptional Elongation Factors