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Titration of essential cellular factors —> DEATH

Figure 17.5. The ERC model for one cause of replicative aging in yeast. As described in the text, one cause of yeast aging is the production of extrachromosomal rDNA circles (ERCs) (Sinclair and Guarente 1997). Each rDNA repeat in the head-to-tail tandem array contains an origin of DNA replication sequence. Intrachromosomal crossing over by homologous recombination can loop out one or more repeats as an extrachromosomal circle. These circles can then replicate as episomal plasmids by virtue of the origin of DNA replication. These types of plasmids do not segregate equally at mitosis, but instead stay with the larger of the two cells at division (the Mother cell in the Mother-Daughter pair). Plasmids thus build up in the Mother cell over subsequent divisions. When plasmids reach large numbers (hundreds per cell), they are thought to compete for essential proteins involved in normal transcription and DNA metabolism, resulting in gene misregulation and cell death. SIR2 protein (Sir2) can repress homologous recombination within the rDNA repeats (Gottlieb and Esposito, 1989), so the relocation of SIR proteins from telomeres to the rDNA can slow this cause of yeast aging. Other causes of yeast cell aging most certainly exist, but the mechanisms by which they cause cells to age are less defined.

proteins from telomeres to the nucleolus prolonging replicative lifespan is that the SIR2 protein released from telomeres can suppress the formation of ERCs. Subsequent work did show that increasing SIR2 protein dosage could increase lifespan, but also indicated that suppression of rDNA recombination was not the only effect of SIR2 protein on lifespan (Kaeberlein et al., 1999). Thus, release of SIR proteins from telomeres may affect yeast lifespan in multiple ways.

The ''silencing configuration'' of long-lived cells established above provided a mechanism to search for other long-lived mutants. A mutation in the MAP kinase encoded by SLT2 was isolated in a screen looking for mutants that have low telomere silencing and higher rDNA silencing. The SLT2 kinase was found to phosphorylate SIR3 protein (Ai et al., 2002; Ray et al., 2003). Mutation of one of the consensus SIR3 protein phosphorylation sites to an unphosphorylatable residue

(SIR3-S275A) caused changes in silencing and an increase in lifespan, which did not appear to occur through an ERC-related mechanism (Ray et al., 2003). Because the SLT2 kinase is activated by continuous cell growth, these results suggested a feedback loop in which rapid growth stimulates SIR3 phosphorylation which shortens lifespan while slower growth (which usually occurs in yeast when nutrients are limiting, i.e., a state resembling caloric restriction) results in extended lifespan. However, the actual mechanism by which lifespan is changed by SIR3 protein phosphorylation is unknown.

The SIR3 phosphorylation story illustrates a second important point in yeast research: the genetic variation between different lab strains. While the ERC model and the SIR3 work were done in the same strain background, subsequent work in another strain that has a longer average lifespan (S288C) found that the SIR3-275A mutation did not cause a significant change in lifespan (Kaeberlein et al., 2005). The genetic differences between these strains are unknown, but must include modifiers of lifespan that can be corrected by mutation of SIR3. As individual humans are genetically diverse, the yeast case illustrates how some changes may increase the lifespan of some individuals but not others. The utility of the yeast model system might be significantly enhanced if the genomic sequences of several common lab yeast strains were known and the genetic differences, and thus potential modifier genes of aging, were identified.

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