It was isolated as a dosage suppressor of a snf1 mig1 srb8 triple mutant, but was later found to regulate gene expression after glucose depletion, when yeast cells shift their metabolism from fermentation of glucose to oxidation of ethanol. This transcriptional response is called the diauxic shift, and affects the expression of more than 2,000 genes in yeast. Induction of several genes at the diauxic shift is dependent on Gis1, which acts through a PDS motif, TAGGGAT, that is present in the promoters of these genes. Gis1 is also required for the induction of several mid-late and late genes during sporulation. Budding yeast also has a fourth related C2H2 zinc finger protein, Rph1, whose sequence is 34% similar to that of Gis1. The zinc fingers of Gis1 and Rph1 are almost identical, which suggests that they should bind to similar DNA motifs. Rph1 was cloned as a repressor of the PHR1 gene encoding photoreactivation lyase. Rph1 and Gis1 redundantly repress PHR1, and also the DPP1 gene encoding diacylglycerol pyrophosphate phosphatase. It is not clear what the roles of Gis1 and Rph1 as repressors of PHR1 and DPP1 have in common with each other, or with the role of Gis1 as an activator in the PDS response. However, several PDS motifs are present in the DPP1 promoter, and a STRE motif is found in PHR1, and there is evidence that the two proteins act through these motifs. Repression by Gis1 and Rph1 thus seems to be mediated at least in part by the same motifs as activation by Gis1. Furthermore, several studies have shown that Rph1 is able to bind the STRE motif. Gis1 and Rph1 also contain JmjN and JmjC domains, which were CP-358774 discovered during a study of Gis1. These domains are found in many eukaryotic proteins, and possess histone demethylase activity, with the catalytic site in the JmjC domain. Paradoxically, while Gis1 appears to have unique functions not shared by Rph1, only the latter has been shown to be an active histone demethylase. Rph1 demethylates di- and trimethylated lysine 36 on histone H3, and surprisingly also H3K9, which is not methylated in yeast. As for Gis1, there have been indications that it may demethylate H3K36me2 and H3K36me1, but there is also data suggesting that it is inactive. The Gis1 JmjC domain has a missense mutation in a key residue, which supports the notion that it is inactive. The JmjC domain is not required for transcriptional activation by Gis1. It is not clear which genes among the targets of Gis1, Msn2 and Msn4 that mediate the effect on aging. One proposed mechanism for life span extension is induction of oxidative stress response genes, such as SOD2. It has also been suggested that reduced nutrient signaling promotes cell cycle arrest, which protects the cells against replicative stress. Moreover, Gcn4- mediated depletion of ribosomal proteins has been implicated in life span extension. Recent work has further shown that the metabolism of glycerol and in particular acetate is important for aging. Yeast cells transiently form acetic acid as glucose is depleted, and acetic acid induced mortality has been proposed to be the primary mechanism of chronological aging. Conversely, glycerol protects yeast cells against stress, and the glycerol biosynthetic genes GPD1, GPD2 and RHR2 are upregulated in sch9, tor1 and ras2 mutants, resulting in higher glycerol levels.