Grant: Travel Awards - Institute Community Support

Dysfunction of telomeres or their interacting factors is linked to genome instability and premature aging. Functions of sirtuin proteins, which are linked to various aging processes, at telomeres are thought to promote lifespan in yeast and mammals. However, replicative lifespan of the budding yeast Saccharomyces cerevisiae shortens upon deletion of Rif1, a protein that limits the recruitment of the sirtuin histone deacetylase Sir2 to telomeres. Here, we show that Rif1 maintains replicative lifespan by ultimately stabilizing another age-related chromosomal domain harboring the ribosomal DNA (rDNA) repeats. Deletion of Rif1 increases Sir2 localization to telomeres and the silent mating-type loci while releasing a pool of the histone deacetylase from the intergenic spacer 1 (IGS1) region of rDNA repeats. This is accompanied by a disruption of silent chromatin assembly at IGS1 and an increase in aberrant recombination events within rDNA repeats. Lifespan defects linked to Rif1 deletion can be prevented in settings where rDNA repeats are forcibly stabilized via deletion of the replication fork blocking protein Fob1. Moreover, Sir2 over-expression prevents Rif1 deletion from excessively reducing Sir2 localization/function at IGS1 and shortening replicative lifespan. In addition, subjecting cells lacking Rif1 to caloric restriction reduces IGS1 histone deacetylation, increases replicative lifespan, and reveals genetic interactions between Rif1 and Sir2 in the cellular response to changes in nutrient levels. Our data indicate that Rif1 maintains lifespan-sustaining levels of Sir2 at rDNA by preventing the excessive recruitment of the histone deacetylase to telomeres and silent mating-type loci. Since sirtuin histone deacetylases such as Sir2 each operate at multiple age-related loci, we propose that factors limiting the localization of sirtuins to certain age-related loci can promote lifespan-sustaining roles of these sirtuins elsewhere in the genome.