First, the role
of Sir2 as a key regulator of yeast lifespan was challenged.24 Second, at that time, no ortholog for PNC1 in other organisms was found. Therefore, the answer as to whether this model is unique only for yeast remains elusive. The first uncertainty about the role Sir2 plays in modulating replicative longevity in yeast via regulation of the rate of ERC quality control formation arose from the observation that the lifespan extension by overexpressing Sir2 was strain-dependent.24 In addition, it was noticed that in the BY4742 yeast strain, mutation of fob1, which blocks the formation of ERCs, Inhibitors,research,lifescience,medical or Sir2 overexpression, together with DR has a cumulative effect on yeast lifespan.24 Put simply, DR extended the lifespan of fob1 or sir2 double mutation. Thus, at least in this yeast strain the effect of DR cannot be Sir2 or ERC-dependent, as an additional increase of lifespan was seen with each treatment. In response to these claims other groups have shown that in the absence of Sir2 another yeast sirtuin, Inhibitors,research,lifescience,medical Hst2, takes over and regulates the positive effect of DR on Inhibitors,research,lifescience,medical yeast lifespan via ERC formation.25 However, this was not the end of the debate. Soon after, two researchers published that in the BY4742 yeast strain, double mutation of sir2 and fob1 along with a mutation in one of the hst isoforms hst1/hst2/hst4 has no significant effect on the yeast lifespan.26
Treatment with DR extended the lifespan of these combinations. Notably, Inhibitors,research,lifescience,medical the role of Hst3 in this study was complex. Mutations in hst3 only, or triple mutation sir2hst3fob1,
have a small but significant effect on yeast lifespan. However, once combined with hst4 mutation, yeast lifespan was significantly reduced. Moreover, DR was not able to extend the lifespan of yeast carrying mutations in fob1 and all yeast sirtuins. Interestingly, the authors did not report whether DR can extend the lifespan Inhibitors,research,lifescience,medical in hst3hst4 double mutations. Thus, the role of hst3 in DR response remains elusive. Taken together, despite extensive research, the question whether Sir2 or other sirtuins regulate yeast lifespan Brefeldin_A during DR via controlling ERCs formation is still under debate. Recent studies have reported that Sir2 regulates yeast replicative lifespan by additional rDNA-independent mechanisms. During cytokinesis, the majority of proteins damaged due to oxidative stress are maintained in the mother cell. Nystrom and his associates showed that Sir2 is required for this asymmetric inheritance, and absence of Sir2 results in an inheritance of oxidatively damaged proteins and reduced selleck chemical Dasatinib capacity to respond to oxidative stress in daughter cells.27 Others have shown that an age-associated decrease in Sir2 protein levels is accompanied by an increase in histone H4 K16 acetylation and regions.