Aneuploidy shortens replicative lifespan in <i>Saccharomyces cerevisiae</i>

Sunshine, Anna B.; Ong, Giang T.; Nickerson, Daniel P.; Carr, Daniel; Murakami, Christopher J.; Wasko, Brian M.; Smerdel-Ramoya, Anna; Merz, Alexey J.; Kaeberlein, Matt; Dunham, Maitreya J.

doi:10.1111/acel.12443

Cited by 22 publications

(18 citation statements)

References 47 publications

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“…These observations are consistent with previous studies showing that acquisition of extra chromosomes leads to proteotoxicity (14,28,29). Moreover, disomic yeast strains containing an extra copy of a single chromosome have been shown to generally have a decreased replicative lifespan (30). Together, these data indicate that protective genes located on duplicated chromosomes are beneficial upon ER stress, but the proteotoxic effect of aneuploidy leads to reduced fitness, as evidenced by shortened lifespan and slow growth.…”

Section: Discussionsupporting

confidence: 91%

Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast

Beaupère

Dinatto

Wasko

et al. 2018

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

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The yeast genome becomes unstable during stress, which often results in adaptive aneuploidy, allowing rapid activation of protective mechanisms that restore cellular homeostasis. In this study, we performed a genetic screen in to identify genome adaptations that confer resistance to tunicamycin-induced endoplasmic reticulum (ER) stress. Whole-genome sequencing of tunicamycin-resistant mutants revealed that ER stress resistance correlated significantly with gains of chromosomes II and XIII. We found that chromosome duplications allow adaptation of yeast cells to ER stress independently of the unfolded protein response, and that the gain of an extra copy of chromosome II alone is sufficient to induce protection from tunicamycin. Moreover, the protective effect of disomic chromosomes can be recapitulated by overexpression of several genes located on chromosome II. Among these genes, overexpression of UDP--acetylglucosamine-1-P transferase (), a subunit of the 20S proteasome (), and induced tunicamycin resistance in wild-type cells, whereas deletion of all three genes completely reversed the tunicamycin-resistance phenotype. Together, our data demonstrate that aneuploidy plays a critical role in adaptation to ER stress by increasing the copy number of ER stress protective genes. While aneuploidy itself leads to proteotoxic stress, the gene-specific effects of chromosome II aneuploidy counteract the negative effect resulting in improved protein folding.

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Section: Discussionsupporting

confidence: 91%

Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast

Beaupère

Dinatto

Wasko

et al. 2018

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

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“…Aneuploidy is frequently observed in eukaryotes and has been shown to affect cellular physiology in organisms from yeast to human 1 . The extra chromosomes delay cellular growth, interfere with embryonic development, increase genomic instability, and promote aging [1][2][3][4][5] . Impaired proliferation is a common feature of any type of karyotype alteration, including aneuploidy 2,6 .…”

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confidence: 99%

Molecular signatures of aneuploidy-driven adaptive evolution

et al. 2020

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Alteration of normal ploidy (aneuploidy) can have a number of opposing effects, such as unbalancing protein abundances and inhibiting cell growth but also accelerating genetic diversification and rapid adaptation. The interplay of these detrimental and beneficial effects remains puzzling. Here, to understand how cells develop tolerance to aneuploidy, we subject disomic (i.e. with an extra chromosome copy) strains of yeast to long-term experimental evolution under strong selection, by forcing disomy maintenance and daily population dilution. We characterize mutations, karyotype alterations and gene expression changes, and dissect the associated molecular strategies. Cells with different extra chromosomes accumulated mutations at distinct rates and displayed diverse adaptive events. They tended to evolve towards normal ploidy through chromosomal DNA loss and gene expression changes. We identify genes with recurrent mutations and altered expression in multiple lines, revealing a variant that improves growth under genotoxic stresses. These findings support rapid evolvability of disomic strains that can be used to characterize fitness effects of mutations under different stress conditions.

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“…BUL1 alleles with loss of function mutation (BUL1 Q146K , BUL1 Q146P ) have been isolated previously (Tardiff et al, 2013;Sunshine et al, 2016). They bear mutations at the same residue near the PY motif (PPSY, 157-160), essential for binding Rsp5 ligase.…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane localization of paralogous leucine permeases Bap2 and Bap3 is regulated by Bul1

Maheswaran

Bhat

2020

Preprint

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AbstractTimeliness in expression and degradation of the nutrient permeases is vital for any organism. In Saccharomyces cerevisiae while transcriptional regulation of permeases has been studied in great detail, post translational events such as trafficking, sorting and turnover are poorly understood. We observed that loss of BAP2 and but no other leucine permeases lead to growth retardation in a routine used SCGlu/Gal but not in a SCGlylac medium. Leucine prototrophy suppressed the growth retardation, showing that BAP2 was synthetically lethal with LEU2. We revealed that loss of BUL1 but not BUL2 an arrestin involved in trafficking of other diverse permeases suppressed this lethality. The suppression was dependent on another leucine permease BAP3. Further experiments revealed that in bul1Δ cells, both BAP2 and BAP3 accumulated in plasma membrane and their turnover is reduced. Based on our results and what is known, we propose that BUL1 regulates TORC1 activity by controlling the leucine uptake.

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Aneuploidy shortens replicative lifespan in Saccharomyces cerevisiae

Cited by 22 publications

References 47 publications

Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast

Genetic screen identifies adaptive aneuploidy as a key mediator of ER stress resistance in yeast

Molecular signatures of aneuploidy-driven adaptive evolution

Plasma membrane localization of paralogous leucine permeases Bap2 and Bap3 is regulated by Bul1

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