Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still incompletely understood. Using budding yeast replicative lifespan as a model for aging in actively dividing cells, we identify nuclear proteins that are depleted in the earliest stages of aging. We find that many age-depleted proteins are involved in ribosome biogenesis, specifically in ribosome processing, or in maintenance of chromatin stability. We focus on topoisomerase I (Top1) as a novel age-depleted nuclear protein and determine that its depletion in the early stages of aging is not a result of transcriptional changes or changes in protein turnover. Despite the stark depletion of Top1 in early aging, we find that rescue of this age-dependent depletion is harmful to replicative lifespan. When overexpressed, Top1 disrupts the stoichiometry of the RENT complex by pulling Sir2 away from the ribosomal DNA (rDNA), a phenotype that is further enhanced when the overexpressed Top1 is catalytically dead. Loss of Sir2 from the rDNA via the overexpression of catalytically dead Top1 decreases RNA Pol II silencing of a reporter gene inside or adjacent to the rDNA, consistent with the lifespan defect. Finally, we show that the catalytic activity of Top1 plays an important role in the establishment of rDNA silencing, raising the possibility that rDNA secondary structure/DNA topology is important for RNA Pol I-dependent spreading of silent chromatin across the rDNA locus.

• PMID: 41419199
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Journal Article

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Power LN, Zawrotna N, Dinda M, Weir AE, Paudel BB, Ghimire O, Kisiel K, Letai CT, Janes KA, Smith JS

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