Replicative Aging Silencing And The Erc Model

A series of papers from the Guarente lab demonstrated that Sir proteins in old yeast cells (i.e., cells that had budded many times) leave silencers and telomeres and move to the nucleolus, the site of rDNA transcription (Kennedy et al., 1997; Smeal et al., 1996). This lab also isolated a SIR4 mutation that truncated the C-terminus and allowed the release of other Sir proteins from telomeres and silencers in young cells (Kennedy et al., 1995). These observations established the aforementioned ''silencing configuration'' for long-lived cells and suggested that events in the nucleolus might play some role in aging. The only known function of Sir proteins in the nucleolus at the time was suppression of rDNA recombination: direct repeats such as the rDNA array are prone to intrachromosomal and interchromosomal recombination that can lengthen and shorten the repeats, and this recombination is repressed in yeast in part by the action of the SIR2 gene product (Gottlieb and Esposito, 1989).

Work by Sinclair and Guarente later established that extrachromosomal rDNA circles (ERCs) can cause one form of yeast aging (Sinclair and Guarente, 1997) (Figure 17.5).

ERCs are episomal plasmids that arise within yeast by means of recombination within the rDNA repeats to loop out a circular form of the repeat. Each repeat contains an origin of DNA replication, and so each circular form can replicate as an extrachromosomal plasmid. Budding yeast divides asymmetrically to produce a large mother cell and a smaller daughter cell, and extrachromosomal plasmids containing just an origin of DNA replication tend to stay with the mother cell at mitosis for unknown reasons (Murray and Szostak, 1983). Thus, once a plasmid is formed, its progeny accumulate in the mother cell quickly. Sinclair and Guarente showed that introduction of these plasmids early in life caused rapid replicative aging. Given the role of SIR2 protein in repressing rDNA recombination, one explanation for the migration of silencing ribosomal DNA repeats

Sir2

Homologous Recombination

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