DNA Replication Stress Is a Determinant of Chronological Lifespan in Budding Yeast

Weinberger, Martin; Li, Feng; Paul, Anita; Smith, Daniel L.; Hontz, Robert D.; Smith, Jeffrey S.; Vujcic, Marija; Singh, Keshav K.; Huberman, Joel A.; Burhans, William C.

doi:10.1371/journal.pone.0000748

Cited by 95 publications

(128 citation statements)

References 88 publications

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“…The overall leftward shift in fluorescence intensity in starving planktonic populations (e.g., Fig. 2A, 17-d) may be evidence of DNA degradation (24); indeed, it has been argued that such cells become apoptotic (25). By contrast, flow cytometry confirmed that immobilized yeast fed ad libitum ceased replicating by day 5, was in G1-like arrest, and was not apoptotic (Fig.…”

Section: Nondividing Well-fed Yeast Shows No Loss In Viability Duringmentioning

confidence: 84%

“…In fact, survivorship of encapsulated rim15Δ mutants is comparable to that of starved planktonic rim15Δ mutants in extended batch culture (20%) (77). Reduced viability of the deletion strain may be attributed to its inability to completely arrest, which leads to replicative stress (24,78), and/or to diminished stress resistance, which is essential for stationary-phase survival. Given that RIM15 is highly expressed in encapsulated but not in planktonic yeast, and given that encapsulated wild-type but not rim15Δ cells cease to reproduce and show extended CLS, we conclude that differential expression of RIM15 facilitates cell cycle arrest and increases stress resistance in immobilized yeast.…”

Section: Growth Arrest and Longevity In Immobilized Yeast May Be Relamentioning

confidence: 97%

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Uncoupling reproduction from metabolism extends chronological lifespan in yeast

Nagarajan

Kruckeberg

Schmidt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Studies of replicative and chronological lifespan in Saccharomyces cerevisiae have advanced understanding of longevity in all eukaryotes. Chronological lifespan in this species is defined as the agedependent viability of nondividing cells. To date this parameter has only been estimated under calorie restriction, mimicked by starvation. Because postmitotic cells in higher eukaryotes often do not starve, we developed a model yeast system to study cells as they age in the absence of calorie restriction. Yeast cells were encapsulated in a matrix consisting of calcium alginate to form ∼3 mm beads that were packed into bioreactors and fed ad libitum. Under these conditions cells ceased to divide, became heat shock and zymolyase resistant, yet retained high fermentative capacity. Over the course of 17 d, immobilized yeast cells maintained >95% viability, whereas the viability of starving, freely suspended (planktonic) cells decreased to <10%. Immobilized cells exhibited a stable pattern of gene expression that differed markedly from growing or starving planktonic cells, highly expressing genes in glycolysis, cell wall remodeling, and stress resistance, but decreasing transcription of genes in the tricarboxylic acid cycle, and genes that regulate the cell cycle, including master cyclins CDC28 and CLN1. Stress resistance transcription factor MSN4 and its upstream effector RIM15 are conspicuously up-regulated in the immobilized state, and an immobilized rim15 knockout strain fails to exhibit the long-lived, growth-arrested phenotype, suggesting that altered regulation of the Rim15-mediated nutrient-sensing pathway plays an important role in extending yeast chronological lifespan under calorie-unrestricted conditions. cell longevity | Ca-alginate encapsulation U nicellular microbes senesce and die (for reviews, see refs.

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Section: Nondividing Well-fed Yeast Shows No Loss In Viability Duringmentioning

confidence: 84%

Section: Growth Arrest and Longevity In Immobilized Yeast May Be Relamentioning

confidence: 97%

Uncoupling reproduction from metabolism extends chronological lifespan in yeast

Nagarajan

Kruckeberg

Schmidt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…In SP cultures, auxotrophs have been shown to be genetically unstable and rely on the DNA damage checkpoint to retain viability (Weinberger et al, 2007). One potential solution to this problem is to add fourfold more of the required compounds than are typically added (Powers et al, 2006;Wei et al, 2008).…”

Section: Ylr108c Ylr338w(opi9) Ymr169c(ald3) Ymr170c(ald2) Ymr2mentioning

confidence: 99%

Budding YeastSSD1-VRegulates Transcript Levels of Many Longevity Genes and Extends Chronological Life Span in Purified Quiescent Cells

Qin

et al. 2009

MBoC

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Ssd1 is an RNA-binding protein that affects literally hundreds of different processes and is polymorphic in both wild and lab yeast strains. We have used transcript microarrays to compare mRNA levels in an isogenic pair of mutant (ssd1-d) and wild-type (SSD1-V) cells across the cell cycle. We find that 15% of transcripts are differentially expressed, but there is no correlation with those mRNAs bound by Ssd1. About 20% of cell cycle regulated transcripts are affected, and most show sharper amplitudes of oscillation in SSD1-V cells. Many transcripts whose gene products influence longevity are also affected, the largest class of which is involved in translation. Ribosomal protein mRNAs are globally down-regulated by SSD1-V. SSD1-V has been shown to increase replicative life span¤ and we show that SSD1-V also dramatically increases chronological life span (CLS). Using a new assay of CLS in pure populations of quiescent prototrophs, we find that the CLS for SSD1-V cells is twice that of ssd1-d cells. INTRODUCTIONSsd1 is an RNA-binding protein (Uesono et al., 1997;Hogan et al., 2008) that can be distinguished from the hundreds of other RNA-binding proteins by its unusual properties. First of all, ssd1 is highly pleiotropic. This locus has at least nine different names because of its having been identified in genetic screens for its effect on minichromosome stability, stress tolerance, membrane trafficking, and cell wall integrity, among other things Kosodo et al., 2001;Vannier et al., 2001;Reinke et al., 2004). Systematic global screens have identified ϳ200 genes that show genetic or physical interactions with Ssd1 (Reguly et al., 2006). These genes show a striking enrichment (Hong et al., 2008) for posttranslational modifiers (p ϭ 10 Ϫ14 ), including 19 kinases and nine histone deacetylases, and genes involved in the cell cycle and cell morphogenesis (p ϭ 10 Ϫ8 ). ssd1 mutants display sensitivity to high osmolarity, caffeine, fungicides¤ and numerous other compounds, which suggests a role for this protein in the maintenance of cell wall integrity (Ibeas et al., 2001;Parsons et al., 2004), but its mechanism of action remains obscure.Despite, or perhaps because of, its impact on so many different cellular functions, SSD1 is a common site of variation in both laboratory strains and natural populations of budding yeast (Wheeler et al., 2003). One possible explanation is that SSD1-V, which encodes the full-length "wildtype" protein, reduces the virulence of Saccharomyces cerevisiae in one mouse model (Wheeler et al., 2003), but SSD1-V is critical in Candida (Gank et al., 2008) and several fungal pathogens of plants for evading their hosts' defense systems (Tanaka et al., 2007). In most cases, genetic interactions with SSD1-V are positive, whereas the premature termination alleles (ssd1-d) cause lethality or a more extreme phenotype. One important exception is the RAM signaling pathway mutants, tao3 (Du and Novick, 2002), and cbk1 (Tong et al., 2001;Jorgensen et al., 2002), whose loss of function is lethal if the SSD1-V a...

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“…Lifespan data did not support this hypothesis, but surprisingly, we found that strains with high Ty1 copy number had extended lifespan when cells were grown either in synthetic medium or in rich medium in the presence of a low dose of the ribonucleotide reductase inhibitor hydroxyurea (HU). Hydroxyurea can stimulate Ty1 mobility and causes DNA replication stress, and replication stress has been correlated with reduced yeast chronological lifespan Weinberger et al 2007Weinberger et al , 2013. However, lifespan extension in high Ty1 copy-number strains did not appear to be due to high retrotransposition levels or substantial differences in DNA replication stress.…”

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confidence: 97%

Extension of Saccharomyces paradoxus Chronological Lifespan by Retrotransposons in Certain Media Conditions Is Associated with Changes in Reactive Oxygen Species

VanHoute

Maxwell

2014

Genetics

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Retrotransposons are mobile DNA elements present throughout eukaryotic genomes that can cause mutations and genome rearrangements when they replicate through reverse transcription. Increased expression and/or mobility of retrotransposons has been correlated with aging in yeast, Caenorhabditis elegans, Drosophila melanogaster, and mammals. The many copies of retrotransposons in humans and various model organisms complicate further pursuit of this relationship. The Saccharomyces cerevisiae Ty1 retrotransposon was introduced into a strain of S. paradoxus that completely lacks retrotransposons to compare chronological lifespans (CLSs) of yeast strains with zero, low, or high Ty1 copy number. Yeast chronological lifespan reflects the progressive loss of cell viability in a nondividing state. Chronological lifespans for the strains were not different in rich medium, but were extended in high Ty1 copy-number strains in synthetic medium and in rich medium containing a low dose of hydroxyurea (HU), an agent that depletes deoxynucleoside triphosphates. Lifespan extension was not strongly correlated with Ty1 mobility or mutation rates for a representative gene. Buffering deoxynucleoside triphosphate levels with threonine supplementation did not substantially affect this lifespan extension, and no substantial differences in cell cycle arrest in the nondividing cells were observed. Lifespan extension was correlated with reduced reactive oxygen species during early stationary phase in high Ty1 copy strains, and antioxidant treatment allowed the zero Ty1 copy strain to live as long as high Ty1 copy-number strains in rich medium with hydroxyurea. This exceptional yeast system has identified an unexpected longevity-promoting role for retrotransposons that may yield novel insights into mechanisms regulating lifespan.

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DNA Replication Stress Is a Determinant of Chronological Lifespan in Budding Yeast

Cited by 95 publications

References 88 publications

Uncoupling reproduction from metabolism extends chronological lifespan in yeast

Uncoupling reproduction from metabolism extends chronological lifespan in yeast

Budding YeastSSD1-VRegulates Transcript Levels of Many Longevity Genes and Extends Chronological Life Span in Purified Quiescent Cells

Extension of Saccharomyces paradoxus Chronological Lifespan by Retrotransposons in Certain Media Conditions Is Associated with Changes in Reactive Oxygen Species

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