Mutations in the RAD27 and SGS1 genes differentially affect the chronological and replicative lifespan of yeast cells growing on glucose and glycerol.
ABSTRACT The Sgs1 protein from Saccharomyces cerevisiae is a member of the RecQ helicases. Defects in RecQ helicases result in premature aging phenotypes in both yeasts and humans, which appear to be promoted by replicative stress. Yeast rad27 mutants also suffer from premature aging. As the human Rad27p and Sgs1p homologs interact, a similar interaction between the yeast proteins could be important for promoting longevity in S. cerevisiae. We tested the contribution of a potential interaction between Rad27p and Sgs1p to longevity by analyzing lifespan and parameters associated with longevity in rad27 and sgs1 mutants. The carbon source supporting growth also modulated longevity as evaluated by replicative and chronological lifespan measurements. Growth on glycerol promoted chronological lifespan, while maximum replicative lifespan was obtained with glucose-supported growth. In comparison to the individual mutants, the sgs1 rad27 double mutant displayed a shortened replicative lifespan and was also more sensitive to DNA-damaging agents. In addition to promoting replicative lifespan, the activity of Rad27p was critical for achieving full chronological lifespan. The rad27 mutants exhibited increased oxidative stress levels along with an elevated spontaneous mutation rate. Removal of Sgs1p activity additionally increased the oxidative stress and spontaneous mutation rate in rad27 mutants without affecting the chronological lifespan.
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ABSTRACT: Manganese is an essential trace element, whose intracellular levels need to be carefully regulated. Mn(2+) acts as a cofactor for many enzymes and excess of Mn(2+) is toxic. Alterations in Mn(2+) homeostasis affect metabolic functions and mutations in the human Mn(2+)/Ca(2+) transporter ATP2C1 have been linked to Hailey-Hailey disease. By deletion of the yeast orthologue PMR1 we have studied the impact of Mn(2+) on cell cycle progression and show that an excess of cytosolic Mn(2+) alters S-phase transit, induces transcriptional up-regulation of cell cycle regulators, bypasses the need for S-phase cell cycle checkpoints and predisposes to genomic instability. On the other hand, we find that depletion of the Golgi Mn(2+) pool requires a functional morphology checkpoint to avoid the formation of polyploid cells.Journal of Biological Chemistry 04/2012; 287(22):18717-29. · 4.65 Impact Factor
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ABSTRACT: Aging affects all organisms, from unicellular yeasts to multicellular humans. Studies in model organisms demonstrate that the pathways that mediate the two forms of aging, replicative and chronological, are highly conserved. Most studies are focused on the effect of aging on an individual cell rather than a whole population. Complex longevity regulation, however, makes aging a highly adaptive trait that is subject to natural selection. Recent studies have shed light on the potential relevance of aging in fungal pathogens, which undergo replicative aging when they expand in the host environment. Hence, pathogens causing chronic infections can constitute ideal model organisms in unraveling the contribution of selection to aging within a population and help elucidate the contribution of aging itself to the virulence of infections.Current opinion in microbiology 04/2013; · 7.87 Impact Factor
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ABSTRACT: In many organisms, attenuation of growth signaling by caloric restriction or mutational inactivation of growth signaling pathways extends lifespan and protects against cancer and other age-related diseases. The focus of many efforts to understand these effects has been on the induction of oxidative stress defenses that inhibit cellular senescence and cell death. Here we show that in the model organism S. cerevisiae, growth signaling induces entry of cells in stationary phase into S phase in parallel with loss of reproductive capacity, which is enhanced by elevated concentrations of glucose. Overexpression of RNR1 encoding a ribonucleotide reductase subunit required for the synthesis of deoxynucleotide triphosphates and DNA replication suppresses the accelerated loss of reproductive capacity of cells cultured in high glucose. The reduced reproductive capacity of these cells is also suppressed by excess threonine, which buffers dNTP pools when ribonucleotide reductase activity is limiting. Caloric restriction or inactivation of the AKT homolog Sch9p inhibits senescence and death in stationary phase cells caused by the DNA replication inhibitor hydroxyurea or by inactivation of the DNA replication and repair proteins Sgs1p or Rad27p. Inhibition of DNA replication stress represents a novel mechanism by which caloric restriction promotes longevity in S. cerevisiae. A similar mechanism may promote longevity and inhibit cancer and other age-related diseases in humans.Cell cycle (Georgetown, Tex.) 03/2013; 12(8). · 5.24 Impact Factor