[FPU2019] Aging, cell cycle control, proteostasis

Protein misfolding and accumulation of proteotoxic aggregates has been mainly associated to neurodegenerative diseases, but there are also some evidences of damage to proliferative tissues. In the last two years we have accumulated enough experimental evidence to propose that prion-like aggregates act as inhibitors of cell proliferation in budding yeast, with direct consequences in cell aging and death. As in many cell types of different origin, prion-like aggregates are asymmetrically distributed during cytokinesis in budding yeast, and we have found that their progressive accumulation through consecutive generations eventually inhibits cell cycle entry and leads the cell to an irreversible senescent state. Since prion-like and proteotoxic aggregates act as chaperone sinks, our data suggest that chaperome alterations would mediate the observed decline in cell proliferation during cell aging. Here we propose (1) to perform a functional analysis of the chaperome under a variety of proteotoxic aggregation conditions; (2) to extend a genetic screen to identify proteotoxicity-protecting genes in aging cells; (3) to analyze the role of RNA-binding proteins and RNA-protein aggregates in cell aging, and (4) to complete an integrative analysis of candidate modulators of proteotoxic aggregation. With these objectives we aim at the identification of key molecules and mechanisms that restrain cell proliferation during cell aging and, hence, at a better understanding of aging at a systems level.