Coupling phenotypic persistence to DNA damage increases genetic diversity in severe stress

Yaakov, Gilad; Lerner, David R.; Bentele, Kajetan; Steinberger, Joseph; Barkai, Naama

doi:10.1038/s41559-016-0016

Cited by 47 publications

(57 citation statements)

References 44 publications

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“…For example, survival in extreme stress is greatly promoted in pre-adapted cells that already expressing stress genes at the time of stress exposure, but such expression has a cost in standard conditions (Lu et al, 2009). Perhaps accounting for this tradeoff, cells have evolved strategies to distinguish a subset of slow-growing cells that are better adapted to stress conditions (Balaban et al, 2004;Levy et al, 2012;Soll and Kraft, 1988;Yaakov et al, 2017), and for activating stress genes upon moderate stress that do not limit growth but anticipate more severe conditions (Gasch et al, 2000;Guan et al, 2012;Levy et al, 2011;Mitchell et al, 2009).…”

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confidence: 99%

Principles of cellular resource allocation revealed by condition-dependent proteome profiling

Metzl-Raz

Kafri

Yaakov

et al. 2017

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Growing cells coordinate protein translation with metabolic rates. Central to this coordination is ribosome production. Ribosomes drive cell growth, but translation of ribosomal proteins competes with production of other proteins. Theory shows that cell growth is maximized when all expressed ribosomes are constantly translating. To examine whether budding yeast function at this limit of full ribosomal usage, we profiled the proteomes of cells growing in different environments. We find that cells produce an excess of ribosomal proteins, amounting to a constant ≈8% of the proteome. Accordingly, ≈25% of ribosomal proteins expressed in rapidly growing cells do not contribute to translation. This fraction increases as growth rate decreases. These excess ribosomal proteins are employed during nutrient upshift or when forcing unneeded expression. We suggest that steadily growing cells prepare for conditions that demand increased translation by producing excess ribosomes, at the expense of lower steady-state growth rate.

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Principles of cellular resource allocation revealed by condition-dependent proteome profiling

Metzl-Raz

Kafri

Yaakov

et al. 2017

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“…4c). In yeast, DNA damage also induces persisters that carry more mutations 34 , as expected under an elevated SOS response leading to mutagenesis. However, in our case – true to the conventional understanding of persistence – we did not find any mutations when we sequenced whole genomes of WT or Mutant persister cells, as well as their hyper-accurate counterparts.…”

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confidence: 89%

Global mistranslation facilitates sampling of beneficial mutations under stress

Samhita

Agashe

2019

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11Mistranslation is typically deleterious, but can sometimes be beneficial. Although a specific 12 mistranslated protein can confer a short-term benefit in a particular environment, the prevalence of high 13 global mistranslation rates remains puzzling given the large overall cost. Here, we show that generalized 14 mistranslation enhances early E. coli survival under various forms of DNA damage, because it leads to 15 early activation of the DNA damage-induced SOS response. Mistranslating cells therefore maintain 16 larger populations, facilitating later sampling of critical beneficial mutations. Thus, under DNA 17 damage, both basal and induced mistranslation (through genetic or environmental means) increase the 18 number of genetically resistant and phenotypically persistent cells. Surprisingly, mistranslation also 19 increases survival at high temperature. This wide-ranging stress resistance relies on Lon protease, which 20 is revealed as a key effector that induces the SOS response in addition to alleviating proteotoxic stress. 21The new links between error-prone protein synthesis, DNA damage, and generalised stress resistance 22 indicate surprising coordination between intracellular stress responses, and suggest a novel hypothesis 23 to explain high global mistranslation rates. 24 25

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“…DNA from the previous step subjected to SPRI cleanup with SPRI beads 2.3x and eluted with 10mM Tris-HCL pH8. DNA libraries for Illumina NextSeq 2500 sequencing were prepared as in Yaakov et al (2017).…”

Section: Methodsmentioning

confidence: 99%

Gene transcription as a limiting factor in protein production and cell growth

Metzl-Raz

Kafri

Yaakov

et al. 2019

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8Growth rate and cell size are principle characteristics of proliferating cells, whose values 9 depend on cellular biosynthetic processes in a way poorly understood. Protein production is 10 critical for growth, and we therefore examined for processes limiting this production. 11Burdening cells with an excess of inert protein changed endogenous gene expression similarly 12 to transcription-perturbing mutants, was epistatic to these mutants, but did not deplete 13 respective factors from gene promoters. Mathematical modeling, corroborated by 14 experiments, attributed this signature to a feedback which proportionally increases all 15 endogenous gene expression, but lags at fast initiating genes already transcribed close to the 16 maximal possible rate. As a possible benefit of maximizing transcription rates, we discuss a 17 conflict between cell growth rate and size, which emerges above a critical cell size set by 18 transcript abundance. We propose that biochemical limits on protein and mRNA production 19 define the characteristic values of cell size and division time. 20 21 22 23 Introduction: 24 Cells tightly control the rate by which different proteins are produced. Regulation of protein 25 expression can be direct, by factors that bind specific regulatory regions, or indirect, through 26 changes in global parameters such as growth rate or cell size that subsequently alter protein 27 expression. Indirect regulation may also occur through the depletion of common resources: 28 when a general machinery is limiting, inducing the expression of specific proteins reduces 29 production of other proteins that compete for the same machinery. Direct regulation of gene 30 expression is extensively studied. By contrast, little is known about indirect regulations within 31 the transcription and translation networks.32 Ribosomes present a potentially limiting resource that determines the rate of protein 33 translation and cell growth. Theory shows that in order to maximize growth rate, cells must tune 34 their proteome compositions, so that they express the maximal number of ribosomes which can 35 still be simultaneously engaged in translation. Under these conditions, in which all expressed 36 ribosomes are constantly translating, growth rate is proportional to ribosome concentration, 37 namely the ribosome:protein ratio. This predicted linear relation between ribosome 38 concentration and cell growth rate was verified experimentally in a large number of cell types Metzl-Raz et al.,major role in transcription initiation and re-initiation, we focused on the rate by which 79 transcription is initiated. We discuss why transcription cannot be initiated at rates that exceed 80 an upper bound, and review data reporting genes transcribed at rates close to this limit. We 81 provide evidence that the transcription profile of the burden cells is attributed to these rapidly 82 transcribed genes: burden initiates a feedback in cells, which proportionally increases the 83 amounts of endogenous mRNAs, but fails to do so at genes already t...

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Coupling phenotypic persistence to DNA damage increases genetic diversity in severe stress

Cited by 47 publications

References 44 publications

Principles of cellular resource allocation revealed by condition-dependent proteome profiling

Principles of cellular resource allocation revealed by condition-dependent proteome profiling

Global mistranslation facilitates sampling of beneficial mutations under stress

Gene transcription as a limiting factor in protein production and cell growth

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