Extrachromosomal rDna Circles A Yeastspecific Aging Mechanism

Several important cellular processes have been implicated in the regulation of yeast replicative aging, including

Handbook of Models for Human Aging

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glucose sensing, DNA damage response, stress response, mitochondrial function, and transcriptional silencing (Bitterman et al., 2003; Jazwinski, 2002; Sinclair et al.,

1998). The roles that some of these processes play in lifespan determination are beginning to be elucidated at a molecular level; however, only one molecular cause of replicative senescence has been demonstrated: the mother cell specific accumulation of extrachromosomal rDNA circles (ERCs).

ERCs are self-replicating circular DNA molecules formed through homologous recombination events at the rDNA (Sinclair and Guarente, 1997). The yeast rDNA is a tandem array of 100-200 copies of a 9.1-kb repeat unit, with each repeat unit containing all of the information needed to code for rRNA precursors. Due to the tandem nature of the rDNA array, homologous pairing and recombination can occur between adjacent repeats, resulting in the formation of ERCs containing one or more repeat units. ERCs can be observed by either 1-D or 2-D gel electrophoresis and Southern blotting with a probe for rDNA sequence, and mutations that block homologous recombination, such as deletion of RAD52, prevent ERC formation (Park et al., 1999).

Once formed, a single ERC has the potential to undergo exponential amplification as a function of mother cell age. The age-associated accumulation of ERCs in yeast is likely due to two features: self-replication and asymmetric segregation. Each rDNA repeat unit contains an origin or replication (ARS element), but lacks a centromere-like sequence (CEN element), resulting in preferential segregation of ERCs to the mother cell during cell division (Sinclair and Guarente, 1997). Quantitation of ERCs in aged cells shows a dramatic increase in ERC levels with age, and artificial induction of a single ERC in a virgin daughter cell, through the use of a CRE recombinase system, shortens life span by about 50% (Sinclair and Guarente, 1997). Thus, ERCs accumulate in normally aging mother cells and can lead to senescence.

An important prediction of the ERC model of yeast aging is that a mutation resulting in decreased ERC formation (or accumulation) should increase life span, assuming said mutation does not also have a detrimental effect on fitness. This prediction was validated with the finding that deletion of FOB1 both dramatically reduces ERC levels and increases mean and maximum life span by approximately 35% (Defossez et al., 1999). The Fob1 protein promotes ERC formation by binding to the rDNA and causing a recombinogenic unidirectional replication fork block (Kobayashi and Horiuchi, 1996). In the absence of Fob1, rDNA recombination is reduced approximately 10-fold (Defossez et al., 1999).

A second protein that regulates yeast replicative life span by altering ERC levels is Sir2 (Kaeberlein et al.,

1999). Sir2 is an NAD+-dependent histone deacetylase (Imai et al., 2000; Landry et al., 2000; Smith et al., 2000; Tanner et al., 2000), conserved from bacteria to man (Blander and Guarente, 2004). In yeast, Sir2, along with

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