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.
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.
Cell Rep. 2023 Jan 31;42(1):111944. doi: 10.1016/j.celrep.2022.111944. Epub 2023 Jan 10.
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.
基因组不稳定性可导致许多生物体衰老。核糖体 RNA 基因（rDNA）簇是基因组中最不稳定的区域之一，该区域的稳定性影响芽殖酵母的复制寿命。为了了解其潜在机制，我们寻找 rDNA 更稳定且寿命长于野生型细胞的酵母突变体。结果表明，转录延伸因子 Spt4 的缺失导致 rDNA 稳定性增加、rDNA 调控 E 启动子的非编码 RNA 转录本水平降低，并以 SIR2 依赖的方式延长复制寿命。在 E 启动子位点不存在非编码 RNA 转录的情况下，Spt4 依赖性的寿命限制被消除。随着细胞衰老，Spt4 的数量增加，其功能变得更加重要。这些发现表明，Spt4 是一种有前途的衰老因子，通过非编码 RNA 转录驱动的 rDNA 不稳定性加速细胞衰老。
