Integrating yeast chemical genomics and mammalian cell pathway analysis

Abstract

Chemical genomics has been applied extensively to evaluate small molecules that modulate biological processes in Saccharomyces cerevisiae. Here, we use yeast as a surrogate system for studying compounds that are active against metazoan targets. Large-scale chemical-genetic profiling of thousands of synthetic and natural compounds from the Chinese National Compound Library identified those with high-confidence bioprocess target predictions. To discover compounds that have the potential to function like therapeutic agents with known targets, we also analyzed a reference library of approved drugs. Previously uncharacterized compounds with chemical-genetic profiles resembling existing drugs that modulate autophagy and Wnt/β-catenin signal transduction were further examined in mammalian cells, and new modulators with specific modes of action were validated. This analysis exploits yeast as a general platform for predicting compound bioactivity in mammalian cells.

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control

“…In addition, mitochondrial proliferation is increased, indicating that also in this unicellular eukaryote, mitochondrial metabolism and functionality may contribute to the induction and/or maintenance of the senescent state [ 135 ]. Although both yeast and C. elegans lack complex traits associated with senescence, these models contributed substantially to our current understanding of fundamental molecular aspects associated with aging and senescence [ 11 , 12 , 15 , 132 ]. Genes identified in such screens were subsequently validated in higher eukaryotic model systems, such as human cultured cells [ 55 , 136 , 137 ], organoids [ 138 , 139 ], and mice [ 140 , 141 ], and promoted the identification of promising molecules for translational approaches [ 55 ].…”

“…that contribute to induction and maintenance of the senescent state are conserved in evolution. Thus, simple and easy‐to‐manipulate model organisms such as the yeast Saccharomyces cerevisiae ( S. cerevisiae ) or the nematode Caenorhabditis elegans ( C. elegans ) are frequently used to elucidate fundamental aspects of cell damage and disruption of homeostasis, which promote senescence in vertebrates [ 10 , 11 , 12 , 13 , 14 , 15 ]. However, there is little evidence for senescence in these simple models, which are evolutionarily quite distant from humans.…”