A key goal of research in aging is to understand mechanisms that limit the replicative potential of cells. The yeast Saccharomyces cerevisiae is an important model organism for studying the molecular basis for limited replicative potential of cells. In this yeast, genomic instability has been implicated in limiting replicative potential. Specifically, the stability of the ribosomal DNA (rDNA) repeat array on chromosome XII has been shown to play a key role in regulating replicative life span. Recombination within the rDNA forms ERCs -extrachromosomal rDNA circles. ERCs are self-replicating and are inherited preferentially by mother cells, as a result of a poorly understood process known as mother cell inheritance bias. It has been proposed that ERC accumulation causes replicative senescence in yeast. An alternative view is that ERC accumulation is not a cause, but a result, of cell replication. Unfortunately, ERCs are difficult to study, primarily because ERCs and chromosomal rDNA differ only in terms of DNA topology. Many questions concerning ERCs are difficult or impossible to address experimentally. To overcome this, we have developed a novel plasmid-based model of ERC inheritance and accumulation. This approach uses recombinant plasmids to """"""""mimic"""""""" ERCs. Our studies have shown that plasmids reduce yeast replicative life span in a manner like ERCs. The goal of this proposal is to use this novel plasmid-based model system to test the hypothesis that ERCs and plasmids are a cause of replicative aging in yeast.
Two specific aims are planned.
Specific Aim 1 proposes to: compare the roles of plasmids and ERCs in reducing life span; measure plasmid and ERC levels in senescent cells; and investigate potential mechanisms by which life span is reduced.
Specific Aim 2 proposes to: investigate mother inheritance cell bias by identifying mutations that impair this process; test the prediction that ERCs are """"""""aging factors"""""""" whose transmission to daughter cells increases with mother cell age; and manipulate plasmid inheritance in order to extend replicative life span. These studies hold the promise of revealing mechanisms that limit replicative potential in all eukaryotic cells, including human cells. An understanding of mechanisms that regulate replicative potential of human cells may lead to interventions that extend this potential. Such interventions would have many applications in human health, from treatment of human diseases to increasing quality of life for the elderly.
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