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Project description:Histone modification affects life span in various organisms. The loss of Histone H3K36 methylation can shorten replicative life span in Saccharomyces cerevisiae. However, budding yeast, as a model organism for aging research, has replicative life span (RLS) and chronological life span (CLS). In this study, we showed that the loss of Histone H3K36 methylation can shorten CLS in Saccharomyces cerevisiae. We identified Ubc3/Bre1 mediates polyubiquitination of Set2 K25 and K530 at log phase and stationary phase, and Bre1 interacts with Ubc3 and Rad6 simultaneously. BRE1 knockout can stabilize Set2 protein to maintain H3K36me3 and regulate the transcription of aging related genes, such as DSE1/DSE2/SUN4/EGT2/SCW11. We also proved that Gcn5-mediated Set2 acetylation regulates Set2 protein stability and chronological aging. Altogether, our study showed that knockout of BRE1 and GCN5 regulate Set2 protein level by mediating the polyubiquitination of Set2 to influence the level of H3K36me3 and the transcription level of aging related genes enriched by H3K36me3, thereby extending the chronological life span.
2023-09-29 | GSE221024 | GEO
Project description:Histone modification affects life span in various organisms. The loss of Histone H3K36 methylation can shorten replicative life span in Saccharomyces cerevisiae. However, budding yeast, as a model organism for aging research, has replicative life span (RLS) and chronological life span (CLS). In this study, we showed that the loss of Histone H3K36 methylation can shorten CLS in Saccharomyces cerevisiae. We identified Ubc3/Bre1 mediates polyubiquitination of Set2 K25 and K530 at log phase and stationary phase, and Bre1 interacts with Ubc3 and Rad6 simultaneously. BRE1 knockout can stabilize Set2 protein to maintain H3K36me3 and regulate the transcription of aging related genes, such as DSE1/DSE2/SUN4/EGT2/SCW11. We also proved that Gcn5-mediated Set2 acetylation regulates Set2 protein stability and chronological aging. Altogether, our study showed that knockout of BRE1 and GCN5 regulate Set2 protein level by mediating the polyubiquitination of Set2 to influence the level of H3K36me3 and the transcription level of aging related genes enriched by H3K36me3, thereby extending the chronological life span.
2023-09-29 | GSE221025 | GEO
Project description:Saccharomyces cerevisiae has directly or indirectly contributed to the identification of arguably more mammalian genes that affect aging than any other model organism. Aging in yeast is assayed primarily by measurement of replicative or chronological life span. Here, we review the genes and mechanisms implicated in these two aging model systems and key remaining issues that need to be addressed for their optimization. Because of its well-characterized genome that is remarkably amenable to genetic manipulation and high-throughput screening procedures, S. cerevisiae will continue to serve as a leading model organism for studying pathways relevant to human aging and disease.
| S-EPMC3392685 | biostudies-literature
Project description:We studied the chronological lifespan of glucose-grown Saccharomyces cerevisiae in relation to the function of intact peroxisomes. We analyzed four different peroxisome-deficient (pex) phenotypes. These included ?pex3 cells that lack peroxisomal membranes and in which all peroxisomal proteins are mislocalized together with ?pex6 in which all matrix proteins are mislocalized to the cytosol, whereas membrane proteins are still correctly sorted to peroxisomal ghosts. In addition, we analyzed two mutants in which the peroxisomal location of the ?-oxidation machinery is in part disturbed. We analyzed ?pex7 cells that contain virtually normal peroxisomes, except that all matrix proteins that contain a peroxisomal targeting signal type 2 (PTS2, also including thiolase), are mislocalized to the cytosol. In ?pex5 cells, peroxisomes only contain matrix proteins with a PTS2 in conjunction with all proteins containing a peroxisomal targeting signal type 1 (PTS1, including all ?-oxidation enzymes except thiolase) are mislocalized to the cytosol. We show that intact peroxisomes are an important factor in yeast chronological aging because all pex mutants showed a reduced chronological lifespan. The strongest reduction was observed in ?pex5 cells. Our data indicate that this is related to the complete inactivation of the peroxisomal ?-oxidation pathway in these cells due to the mislocalization of thiolase. Our studies suggest that during chronological aging, peroxisomal ?-oxidation contributes to energy generation by the oxidation of fatty acids that are released by degradation of storage materials and recycled cellular components during carbon starvation conditions.
| S-EPMC3824234 | biostudies-literature
Project description:Calorie restriction extends life span in organisms as diverse as yeast and mammals through incompletely understood mechanisms.The role of NAD+-dependent deacetylases known as Sirtuins in this process, particularly in the yeast Saccharomyces cerevisiae, is controversial. We measured chronological life span of wild-type and sir2Δ strains over a higher glucose range than typically used for studying yeast calorie restriction. sir2Δ extended life span in high glucose complete minimal medium and had little effect in low glucose medium, revealing a partial role for Sir2 in the calorie-restriction response under these conditions. Experiments performed on cells grown in rich medium with a newly developed genetic strategy revealed that sir2Δ shortened life span in low glucose while having little effect in high glucose, again revealing a partial role for Sir2 In complete minimal media, Sir2 shortened life span as glucose levels increased; whereas in rich media, Sir2 extended life span as glucose levels decreased. Using a genetic strategy to measure the strength of gene silencing at HML, we determined increasing glucose stabilized Sir2-based silencing during growth on complete minimal media. Conversely, increasing glucose destabilized Sir-based silencing during growth on rich media, specifically during late cell divisions. In rich medium, silencing was far less stable in high glucose than in low glucose during stationary phase. Therefore, Sir2 was involved in a response to nutrient cues including glucose that regulates chronological aging, possibly through Sir2-dependent modification of chromatin or deacetylation of a nonhistone protein.
| S-EPMC5340332 | biostudies-literature
Project description:The nucleolus is speculated to be a regulator of cellular senescence in numerous biological systems (Guarente, Genes Dev 11(19):2449-2455, 1997; Johnson et al., Curr Opin Cell Biol 10(3):332-338, 1998). In the budding yeast Saccharomyces cerevisiae, alterations in nucleolar architecture, the redistribution of nucleolar protein and the accumulation of extrachromosomal ribosomal DNA circles (ERCs) during replicative aging have been reported. However, little is known regarding rDNA stability and changes in nucleolar activity during chronological aging (CA), which is another yeast aging model used. In the present study, the impact of aberrant cell cycle checkpoint control (knock-out of BUB1, BUB2, MAD1 and TEL1 genes in haploid and diploid hemizygous states) on CA-mediated changes in the nucleolus was studied. Nucleolus fragmentation, changes in the nucleolus size and the nucleolus/nucleus ratio, ERC accumulation, expression pattern changes and the relocation of protein involved in transcriptional silencing during CA were revealed. All strains examined were affected by oxidative stress, aneuploidy (numerical rather than structural aberrations) and DNA damage. However, the bub1 cells were the most prone to aneuploidy events, which may contribute to observed decrease in chronological lifespan. We postulate that chronological aging may be affected by redox imbalance-mediated chromosome XII instability leading to both rDNA instability and whole chromosome aneuploidy. CA-mediated nucleolus fragmentation may be a consequence of nucleolus enlargement and/or Nop2p upregulation. Moreover, the rDNA content of chronologically aging cells may be a factor determining the subsequent replicative lifespan. Taken together, we demonstrated that the nucleolus state is also affected during CA in yeast.
| S-EPMC4019837 | biostudies-literature
Project description:The chronological lifespan of budding yeast is a model of aging and age-related diseases. This paradigm has recently allowed genome-wide screening of genetic factors underlying post-mitotic viability in a simple unicellular system, which underscores its potential to provide a comprehensive view of the aging process. However, results from different large-scale studies show little overlap and typically lack quantitative resolution to derive interactions among different aging factors. We previously introduced a sensitive, parallelizable approach to measure the chronological-lifespan effects of gene deletions based on the competitive aging of fluorescence-labeled strains. Here, we present a thorough description of the method, including an improved multiple-regression model to estimate the association between death rates and fluorescent signals, which accounts for possible differences in growth rate and experimental batch effects. We illustrate the experimental procedure-from data acquisition to calculation of relative survivorship-for ten deletion strains with known lifespan phenotypes, which is achieved with high technical replicability. We apply our method to screen for gene-drug interactions in an array of yeast deletion strains, which reveals a functional link between protein glycosylation and lifespan extension by metformin. Competitive-aging screening coupled to multiple-regression modeling provides a powerful, straight-forward way to identify aging factors in yeast and their interactions with pharmacological interventions.
| S-EPMC7240105 | biostudies-literature
Project description:Migration of fragmented mitochondrial DNA (mtDNA) to the nucleus has been shown to occur in multiple species including yeast, plants, and mammals. Several human diseases, including Pallister-Hall syndrome and mucolipidosis, can be initiated by mtDNA insertion mutagenesis of nuclear DNA. In yeast, we demonstrated that the rate of mtDNA fragments translocating to the nucleus increases during chronological aging. The yeast chronological lifespan (CLS) is determined by the survival of nondividing cell populations. Whereas yeast strains with elevated migration rates of mtDNA fragments to the nucleus showed accelerated chronological aging, strains with decreased mtDNA transfer rates to the nucleus exhibited an extended CLS. Although one of the most popular theories of aging is the free radical theory, migration of mtDNA fragments to the nucleus may also contribute to the chronological aging process by possibly increasing nuclear genomic instability in cells with advanced age.
| S-EPMC3394387 | biostudies-literature
Project description:Aging is a complex trait of broad scientific interest, especially because of its intrinsic link with common human diseases. Pioneering work on aging-related mechanisms has been made in Saccharomyces cerevisiae, mainly through the use of deletion collections isogenic to the S288c reference strain. In this study, using a recently published high-throughput approach, we quantified chronological life span (CLS) within a collection of 58 natural strains across seven different conditions. We observed a broad aging variability suggesting the implication of diverse genetic and environmental factors in chronological aging control. Two major Quantitative Trait Loci (QTLs) were identified within a biparental population obtained by crossing two natural isolates with contrasting aging behavior. Detection of these QTLs was dependent upon the nature and concentration of the carbon sources available for growth. In the first QTL, the RIM15 gene was identified as major regulator of aging under low glucose condition, lending further support to the importance of nutrient-sensing pathways in longevity control under calorie restriction. In the second QTL, we could show that the SER1 gene, encoding a conserved aminotransferase of the serine synthesis pathway not previously linked to aging, is causally associated with CLS regulation, especially under high glucose condition. These findings hint toward a new mechanism of life span control involving a trade-off between serine synthesis and aging, most likely through modulation of acetate and trehalose metabolism. More generally it shows that genetic linkage studies across natural strains represent a promising strategy to further unravel the molecular basis of aging.
| S-EPMC5845861 | biostudies-literature
Project description:Bre1, a conserved E3 ubiquitin ligase in Saccharomyces cerevisiae, together with its interacting partner Lge1, are responsible for histone H2B monoubiquitination, which regulates transcription, DNA replication, and DNA damage response and repair, ensuring the structural integrity of the genome. Deletion of BRE1 or LGE1 also results in whole chromosome instability. We discovered a novel role for Bre1, Lge1 and H2Bub1 in chromosome segregation and sister chromatid cohesion. Bre1's function in G1 and S phases contributes to cohesion establishment, but it is not required for cohesion maintenance in G2 phase. Bre1 is dispensable for the loading of cohesin complex to chromatin in G1, but regulates the localization of replication factor Mcm10 and cohesion establishment factors Ctf4, Ctf18 and Eco1 to early replication origins in G1 and S phases, and promotes cohesin subunit Smc3 acetylation for cohesion stabilization. H2Bub1 epigenetically marks the origins, potentially signaling the coupling of DNA replication and cohesion establishment.
| S-EPMC5699866 | biostudies-literature