Trehalose Is a Key Determinant of the Quiescent Metabolic State That Fuels Cell Cycle Progression upon Return to Growth

Shi, Lei; Sutter, Benjamin M.; Ye, Xinyue; Tu, Benjamin P.

doi:10.1091/mbc.e10-01-0056

Cited by 123 publications

(150 citation statements)

References 37 publications

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“…Another possible and not mutually exclusive role for the YMC could be the periodic degradation of mistranslated and damaged proteins, because autophagy and vacuolar genes peak during the LOC, right after the biosynthesis phase (HOC). The accumulation of reserved carbohydrates during the LOC, which was reported with the discovery of the YMC (4) and confirmed recently (19), likely imposes a fundamental limit on the duration of the LOC required for accumulating enough trehalose in glucose-limited conditions, and on the duration of the HOC given the pool size of reserved carbohydrates. The metabolic synchrony at the level of the culture likely requires cell-cell communication, which we do not yet understand.…”

Section: Discussionmentioning

confidence: 73%

Metabolic cycling without cell division cycling in respiring yeast

Slavov

Macinskas

Caudy

et al. 2011

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

104

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Despite rapid progress in characterizing the yeast metabolic cycle, its connection to the cell division cycle (CDC) has remained unclear. We discovered that a prototrophic batch culture of budding yeast, growing in a phosphate-limited ethanol medium, synchronizes spontaneously and goes through multiple metabolic cycles, whereas the fraction of cells in the G1/G0 phase of the CDC increases monotonically from 90 to 99%. This demonstrates that metabolic cycling does not require cell division cycling and that metabolic synchrony does not require carbon-source limitation. More than 3,000 genes, including most genes annotated to the CDC, were expressed periodically in our batch culture, albeit a mere 10% of the cells divided asynchronously; only a smaller subset of CDC genes correlated with cell division. These results suggest that the yeast metabolic cycle reflects a growth cycle during G1/G0 and explains our previous puzzling observation that genes annotated to the CDC increase in expression at slow growth.T wo kinds of periodic behavior have been characterized in slowly growing yeast cultures. The first, the classical cell division cycle (CDC), consists of four phases (G0/G1, S, G2, and M) that are easily distinguished by morphological criteria. When the growth rate of budding yeast is slowed by mutations or chemicals inhibiting growth, the duration of the G1/G0 phase increases relative to the durations of the S, G2, and M phases (1). Recently, we confirmed and quantified this CDC trend (Fig. 1A) in chemostat cultures whose steady-state growth rate was controlled by limiting natural nutrients (2, 3). The second kind of cycle, the yeast metabolic cycle (YMC), was first observed more than four decades ago (4) as periodic oscillations in the oxygen consumption of continuous, glucose-limited cultures growing in a chemostat. Like the CDC, the YMC can be divided phenomenologically into two phases: the low oxygen consumption phase (LOC), when the amount of oxygen in the medium is high because the cells consume little oxygen, and the high oxygen consumption phase (HOC), when the reverse holds (SI Appendix). We also reported previously (3) similar growth-rate changes in the relative durations of the phases of the YMC (Fig. 1B). As the growth rate increases, the relative duration of the LOC decreases whereas the relative duration of the HOC increases (Fig. 1B), similarly to the analogous changes in the CDC.These changes in the relative durations of the phases affect the composition of asynchronous cultures, because single cells from asynchronous cultures cycle metabolically (5, 6) and thus the fraction of cells in a particular phase is proportional to the duration of that phase relative to the entire cycle period. The increase in the relative duration of a phase results in the increase in the fraction of cells in that phase, and thus an increase in the population-average expression levels of genes peaking during that phase. Consider, for example, a ribosomal gene that peaks in expression during the HOC phase; at slow growt...

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Section: Discussionmentioning

confidence: 73%

Metabolic cycling without cell division cycling in respiring yeast

Slavov

Macinskas

Caudy

et al. 2011

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

104

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“…Budding yeast cells accumulate substantial amounts of the storage carbohydrates trehalose and glycogen upon entry into stationary phase or quiescence (69,70). They then break down these carbohydrate stores to produce glucose, providing a "finishing kick" to Start for reentry into growth (70,71).…”

Section: Discussionmentioning

confidence: 99%

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Shi

2013

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

Self Cite

122

125

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In budding yeast cells, nutrient repletion induces rapid exit from quiescence and entry into a round of growth and division. The G1 cyclin CLN3 is one of the earliest genes activated in response to nutrient repletion. Subsequent to its activation, hundreds of cellcycle genes can then be expressed, including the cyclins CLN1/2 and CLB5/6. Although much is known regarding how CLN3 functions to activate downstream targets, the mechanism through which nutrients activate CLN3 transcription in the first place remains poorly understood. Here we show that a central metabolite of glucose catabolism, acetyl-CoA, induces CLN3 transcription by promoting the acetylation of histones present in its regulatory region. Increased rates of acetyl-CoA synthesis enable the Gcn5p-containing Spt-AdaGcn5-acetyltransferase transcriptional coactivator complex to catalyze histone acetylation at the CLN3 locus alongside ribosomal and other growth genes to promote entry into the cell division cycle.growth control | metabolism | epigenetics T he most basic building blocks of biological organisms are smallmolecule metabolites. In recent years, there has been renewed interest in understanding how the fundamental processes of cell growth and proliferation are coordinated with cellular metabolism. Nutrient-starved yeast cells arrest in a quiescent, or G0, phase of the cell division cycle. Addition of nutrients stimulates exit from the G0 and transition into the G1 phase, and then ∼800 genes are periodically transcribed as a function of the cell cycle (1, 2). CLN3 is observed to be one of the earliest genes transcribed within this set (1-3). Cln3p regulates G1 length by coordinating growth and division and may influence cell size when passing Start, the point at which cells commit to division (4-7). In cln3Δ mutants, cells become larger and stay in the G1 phase longer, resulting in decreased growth and budding rates compared with WT (8, 9) (Fig. S1). Following CLN3 activation, the G1 transcription complexes Swi4p-Swi6p (SBF) and Mbp1-Swi6p (MBF) can be activated by CLN3/CDC28-catalyzed phosphorylation of the SBF inhibitor Whi5p (10-12), and other unknown mechanisms, to enable transcription of over 200 downstream cell-cycle genes (13), including CLN1/2 and CLB5/6. Cln1p and Cln2p can then further enhance SBF-and MBF-dependent G1 transcription through positive feedback mechanisms (14)(15)(16)(17)(18)(19)(20).Although many studies have focused on the mechanisms by which Cln3p regulates G1 transcription, the mechanisms that lead to transcriptional activation of CLN3 itself still remain unresolved. Since the discovery of CLN3 more than 20 y ago (6, 7), the gene and its encoded protein have been reported to be regulated at multiple levels. At the transcriptional level, CLN3 is activated by glucose (21, 22), which is reportedly mediated by Azf1p, a zinc-finger transcription factor (23). Following transcription, CLN3 mRNA availability is regulated by a RNAbinding protein, Whi3p (24). At the translational level, CLN3 is regulated by TOR (target of rapamyc...

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“…Trehalose accumulates in stationary-phase cells and is thought to provide protection against various stresses in the quiescent state (Gray et al 2004;Shi et al 2010). Moreover, trehalose is one of the few metabolites whose levels are anti-correlated with growth rate over all growth-limiting conditions examined (Boer et al 2010).…”

Section: Different Starvation Regimens Yield Different Metabolic Profmentioning

confidence: 99%

Yeast cells can access distinct quiescent states

et al. 2011

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We conducted a phenotypic, transcriptional, metabolic, and genetic analysis of quiescence in yeast induced by starvation of prototrophic cells for one of three essential nutrients (glucose, nitrogen, or phosphate) and compared those results with those obtained with cells growing slowly due to nutrient limitation. These studies address two related questions: (1) Is quiescence a state distinct from any attained during mitotic growth, and (2) does the nature of quiescence differ depending on the means by which it is induced? We found that either limitation or starvation for any of the three nutrients elicits all of the physiological properties associated with quiescence, such as enhanced cell wall integrity and resistance to heat shock and oxidative stress. Moreover, the starvations result in a common transcriptional program, which is in large part a direct extrapolation of the changes that occur during slow growth. In contrast, the metabolic changes that occur upon starvation and the genetic requirements for surviving starvation differ significantly depending on the nutrient for which the cell is starved. The genes needed by cells to survive starvation do not overlap the genes that are induced upon starvation. We conclude that cells do not access a unique and discrete G 0 state, but rather are programmed, when nutrients are scarce, to prepare for a range of possible future stressors. Moreover, these survival strategies are not unique to quiescence, but are engaged by the cell in proportion to nutrient scarcity.

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Trehalose Is a Key Determinant of the Quiescent Metabolic State That Fuels Cell Cycle Progression upon Return to Growth

Cited by 123 publications

References 37 publications

Metabolic cycling without cell division cycling in respiring yeast

Metabolic cycling without cell division cycling in respiring yeast

Acetyl-CoA induces transcription of the key G1 cyclin CLN3 to promote entry into the cell division cycle in Saccharomyces cerevisiae

Yeast cells can access distinct quiescent states

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