Regulation of Ribosomal RNA stability and Its Role in cellular senescence and Evolutionary Adaptability in Yeast
During evolution, the number of genes and cell size increased, and the overall complexity of the organism increased along with them. These evolutionary changes are thought to require more ribosomes to support an increased level of protein synthesis. As the result, the genes encoding ribosomal RNA became the most abundant genes in the eukaryotic genome. They reside in tandem repetitive clusters, in some cases totaling hundreds of copies. Due to their repetitive structure and highly active transcription, the ribosomal RNA gene repeats (rDNA) are some of the most fragile sites in the chromosome and are linked to cellular functions in yeast and mammals.
A unique gene amplification system of the rDNA has developed to compensate for loss of copies. We revealed the basic mechanism of rDNA amplification. In the mechanism, amplification recombination is induced by inhibition of DNA replication and non-coding transcription. Interestingly, we also found that unstable rDNA induces cellular senescence and shorten the lifespan while stabilized rDNA extends it. I present a hypothesis called “rDNA theory for
aging”. In the hypothesis, I speculate the rDNA works as a sensor to monitor genome instability and induces cellular senescence that prevents tumorigenesis.
To identify factors that could connect reduced genome stability in rDNA to senescence, we screened ~5,000 strains of a Saccharomyces cerevisiae deletion library and found ~700 genes that were important for the upkeep of rDNA. These included, as expected, genes associated with chromosome organization, DNA repair and recombination. Surprisingly, deletion of many genes not related to genome maintenance had a marked effect on rDNA structure.
Our screening results suggested several genes instrumental in the production of an aging signal. In the absence of some of these genes, the connection between rDNA instability and senescence was lost. I talk about a mechanism that explains how molecular events at the heart of the replication fork induce abnormal rDNA recombination and are responsible for the emergence of an aging signal.