Department of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States; UCSD Moores Cancer Center, University of California San, Diego, La Jolla, United States
Jeff Hasty
Department of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States; Department of Bioengineering, University of California, San Diego, La Jolla, United States; Synthetic Biology Institute, University of California, San Diego, La Jolla, United States
Department of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States; Department of Bioengineering, University of California, San Diego, La Jolla, United States; Synthetic Biology Institute, University of California, San Diego, La Jolla, United States
Chromatin instability and protein homeostasis (proteostasis) stress are two well-established hallmarks of aging, which have been considered largely independent of each other. Using microfluidics and single-cell imaging approaches, we observed that, during the replicative aging of Saccharomyces cerevisiae, a challenge to proteostasis occurs specifically in the fraction of cells with decreased stability within the ribosomal DNA (rDNA). A screen of 170 yeast RNA-binding proteins identified ribosomal RNA (rRNA)-binding proteins as the most enriched group that aggregate upon a decrease in rDNA stability induced by inhibition of a conserved lysine deacetylase Sir2. Further, loss of rDNA stability induces age-dependent aggregation of rRNA-binding proteins through aberrant overproduction of rRNAs. These aggregates contribute to age-induced proteostasis decline and limit cellular lifespan. Our findings reveal a mechanism underlying the interconnection between chromatin instability and proteostasis stress and highlight the importance of cell-to-cell variability in aging processes.
