DNA replication stress-induced loss of reproductive capacity in<i>S. cerevisiae</i>and its inhibition by caloric restriction

Weinberger, Martin; Sampaio‐Marques, Belém; Ludovico, Paula; Burhans, William C.

doi:10.4161/cc.24232

Cited by 16 publications

(27 citation statements)

References 57 publications

(80 reference statements)

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“…The increased lifespan of all the S. paradoxus strains due to treatment with a low dose of HU is in contrast to a recent report of decreased CLS in S. cerevisiae strains treated with the same dose of HU (Weinberger et al 2013). This discrepancy could be due to differences in methods, but we note that there are certain consistencies between our results and those of the previous report.…”

Section: Discussioncontrasting

confidence: 57%

“…This discrepancy could be due to differences in methods, but we note that there are certain consistencies between our results and those of the previous report. First, S. cerevisiae cells exposed to 30 mM HU have substantially decreased reproductive potential (ability to form colonies on fresh medium) in stationary phase but no reduction in terminal cell density (Weinberger et al 2013). We also observed no decrease in terminal cell density and a moderately lower density of colony forming units (lower reproductive potential) at the start of stationary phase with HU treatment (data not shown).…”

Section: Discussionmentioning

confidence: 60%

“…A metabolic pathway involving threonine has been proposed to buffer deoxynucleoside triphosphate (dNTP) levels in the presence of HU or when other means are used to inhibit ribonucleotide reductase activity (Hartman 2007). Also, thr1Δ mutants have been reported to have decreased CLS, which can be suppressed by overexpression of the ribonucleotide reductase subunit gene RNR1, and excess threonine can suppress the shortened CLS of cells experiencing replication stress due to high glucose (Weinberger et al 2013). Strains were grown and aged in rich medium with four times the normal concentration of threonine to determine whether buffering dNTP levels would result in more similar lifespans for zero and high Ty1 copy strains in the presence of HU.…”

Section: Resultsmentioning

confidence: 99%

“…Increased DNA replication stress has been correlated with decreased yeast CLS (Weinberger et al 2007(Weinberger et al , 2013), so we repeated CLS experiments in YPD medium with a low concentration (30 mM) of the ribonucleotide reductase inhibitor HU. This concentration of HU led to a 30-40% increase in the doubling time of all strains (Table 1), but did not decrease viability when cells first reached stationary phase.…”

Section: Resultsmentioning

confidence: 99%

“…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: 99%

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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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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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Yeast at the Forefront of Research on Ageing and Age-Related Diseases

Sampaio‐Marques

Burhans

Ludovico

2019

Progress in Molecular and Subcellular Biology

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Ageing is a complex and multifactorial process driven by genetic, environmental and stochastic factors that lead to the progressive decline of biological systems. Mechanisms of ageing have been extensively investigated in various model organisms and systems generating fundamental advances. Notably, studies on yeast ageing models have made numerous and relevant contributions to the progress in the field. Different longevity factors and pathways identified in yeast have then been shown to regulate molecular ageing in invertebrate and mammalian models. Currently the best candidates for anti-ageing drugs such as spermidine and resveratrol or anti-ageing interventions such as caloric restriction were first identified and explored in yeast. Yeasts have also been instrumental as models to study the cellular and molecular effects of proteins associated with age-related diseases such as Parkinson's, Huntington's or Alzheimer's diseases. In this chapter, a review of the advances on ageing and age-related diseases research in yeast models will be made. Particular focus will be placed on key longevity factors, ageing hallmarks and interventions that slow ageing, both yeast-specific and those that seem to be conserved in multicellular organisms. Their impact on the pathogenesis of age-related diseases will be also discussed.

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