Translational control during cell division determines when cells start a new cell cycle, how fast they complete it, the number of successive divisions, and how cells coordinate proliferation with available nutrients. The translational efficiencies of mRNAs in cells progressing synchronously through the mitotic cell cycle, while preserving the coupling of cell division with cell growth, remain uninvestigated. We now report comprehensive ribosome profiling of a yeast cell size series from the time of cell birth, to identify mRNAs under periodic translational control. The data reveal coordinate translational activation of mRNAs encoding lipogenic enzymes late in the cell cycle including Acc1p, the rate-limiting enzyme acetyl-CoA carboxylase. An upstream open reading frame (uORF) confers the translational control of and adjusts Acc1p protein levels in different nutrients. The uORF is relevant for cell division because its ablation delays cell cycle progression, reduces cell size, and suppresses the replicative longevity of cells lacking the Sch9p protein kinase regulator of ribosome biogenesis. These findings establish an unexpected relationship between lipogenesis and protein synthesis in mitotic cell divisions.
In several systems, including budding yeast, cell cycle-dependent changes in the transcriptome are well studied. In contrast, few studies queried the proteome during cell division. There is also little information about dynamic changes in metabolites and lipids in the cell cycle. Here, the authors present such information for dividing yeast cells.
A long-standing problem is how cells that lack one of the highly similar ribosomal proteins (RPs) often display distinct phenotypes. Yeast and other organisms live longer when they lack specific ribosomal proteins, especially of the large 60S subunit of the ribosome. However, longevity is neither associated with the generation time of RP deletion mutants nor with bulk inhibition of protein synthesis. Here, we queried actively dividing RP mutants through the cell cycle. Our data link transcriptional, translational, and metabolic changes to phenotypes associated with the loss of paralogous RPs. We uncovered translational control of transcripts encoding enzymes of methionine and serine metabolism, which are part of one-carbon (1C) pathways. Cells lacking Rpl22Ap, which are long-lived, have lower levels of metabolites associated with 1C metabolism. Loss of 1C enzymes increased the longevity of wild type cells. 1C pathways exist in all organisms and targeting the relevant enzymes could represent longevity interventions.
Kes1/Osh4 is a member of the conserved, but functionally enigmatic, oxysterol binding protein-related protein (ORP) superfamily that inhibits phosphatidylinositol transfer protein (Sec14)-dependent membrane trafficking through the trans-Golgi (TGN)/endosomal network. We now report that Kes1, and select other ORPs, execute cell-cycle control activities as functionally non-redundant inhibitors of the G/S transition when cells confront nutrient-poor environments and promote replicative aging. Kes1-dependent cell-cycle regulation requires the Greatwall/MASTL kinase ortholog Rim15, and is opposed by Sec14 activity in a mechanism independent of Kes1/Sec14 bulk membrane-trafficking functions. Moreover, the data identify Kes1 as a non-histone target for NuA4 through which this lysine acetyltransferase co-modulates membrane-trafficking and cell-cycle activities. We propose the Sec14/Kes1 lipid-exchange protein pair constitutes part of the mechanism for integrating TGN/endosomal lipid signaling with cell-cycle progression and hypothesize that ORPs define a family of stage-specific cell-cycle control factors that execute tumor-suppressor-like functions.
Continuously dividing cells coordinate their growth and division. How fast cells grow in mass determines how fast they will multiply. Yet, there are few, if any, examples of a metabolic pathway that actively drives a cell cycle event instead of just being required for it. Here, we show that translational upregulation of lipogenic enzymes in Saccharomyces cerevisiae increased the abundance of lipids and promoted nuclear elongation and division. De-repressing translation of acetyl CoA carboxylase and fatty acid synthase also suppressed cell cycle-related phenotypes, including delayed nuclear division, associated with Sec14p phosphatidylinositol transfer protein deficiencies, and the irregular nuclear morphologies of mutants defective in phosphatidylinositol 4-OH kinase activities. Our results show that increased lipogenesis drives a critical cell cycle landmark and report a phosphoinositide signaling axis in control of nuclear division. The broad conservation of these lipid metabolic and signaling pathways raises the possibility these activities similarly govern nuclear division in other eukaryotes. In this report, the authors show that increasing lipid synthesis promotes the division of the nucleus in yeast cells, a model eukaryotic organism. They also implicate phosphoinositide signaling in the control of nuclear division. Because lipid metabolic and signaling pathways are highly conserved, it is possible that these activities also control nuclear division in other organisms. AUTHOR SUMMARY In this report, the authors show that increasing lipid synthesis promotes the division of the nucleus in yeast cells, a model eukaryotic organism. They also implicate phosphoinositide signaling in the control of nuclear division. Because lipid metabolic and signaling pathways are highly conserved, it is possible that these activities also control nuclear division in other organisms.
The question of what determines whether cells are big or small has been the focus of many studies because it is thought that such determinants underpin the coupling of cell growth with cell division. In contrast, what determines the overall pattern of how cell size is distributed within a population of wild type or mutant cells has received little attention. Knowing how cell size varies around a characteristic pattern could shed light on the processes that generate such a pattern and provide a criterion to identify its genetic basis. Here, we show that cell size values of wild type Saccharomyces cerevisiae cells fit a gamma distribution, in haploid and diploid cells, and under different growth conditions. To identify genes that influence this pattern, we analyzed the cell size distributions of all single-gene deletion strains in Saccharomyces cerevisiae. We found that yeast strains which deviate the most from the gamma distribution are enriched for those lacking gene products functioning in gene expression, especially those in transcription or transcription-linked processes. We also show that cell size is increased in mutants carrying altered activity substitutions in Rpo21p/Rpb1, the largest subunit of RNA polymerase II (Pol II). Lastly, the size distribution of cells carrying extreme altered activity Pol II substitutions deviated from the expected gamma distribution. Our results are consistent with the idea that genetic defects in widely acting transcription factors or Pol II itself compromise both cell size homeostasis and how the size of individual cells is distributed in a population.
Photoaldrin, photodieldrin, and photoheptachlor are more toxic than their corresponding parent compounds (aldrin, dieldrin, and heptachlor) to freshwater invertebrates and vertebrates, and to adult houseflies. The increase in toxicity is very significant in the case of the amphipod, Gammarus (1.5-12 times), bluegill fry (3.6 5.7 times), mosquito larvae, Aedas (2.3-6 times), minnow fry (2.5 times), and the isopid, Asellus (2 times). The greatest increases occur with photodieldrin which is 12 and 5 times more toxic than dieldrin, respectively, to Gammarus, and to bluegill fry, and with photoatdrin which is 6 and 4 times more toxic than aldrin, respectively, to mosquito larvae and bluegill fry. The toxicities of the photoisomers of isodrin and chlordene are generally less than those of their parent compounds to all the organisms tested. The basis of the differences in toxicities of the chlorinated cyclodiene photoisomers appears to be related to their chemical structure which possibly affects their action at the site(s) of toxic action and/or detoxication. The acidic proton present at the secondary chloride in photoatdrin, photodieldrin, and photoheptachlor possibly is responsible for the formation of charge-transfer complexes between components of the nerve and the mixed-function oxidase; the latter enzyme apparently dehydrochlorinates these photo products to their corresponding, more toxic ketones. The absence of such protons in photoisodrin and photochlordene renders them incapable of forming such ketones. The inhibition of these reactions by sesamex in house flies increases the stability of the chlorinated cyclodiene insecticides and, thus, significantly affects their toxicity. The conversion of photoaldrin, photodieldrin, and photoheptachlor to more-toxic and lipophilic ketones warrants additional studies of their accumulation and subsequent concentration by the food chain.The photolysis of chlorinated cyclodiene insecticide chemicals has been reported by workers in several laboratories (Rosen and Sutherland 1966, Rosen et al. 1969, Henderson and Crosby 1967, Khan et al., Benson et al. 1971. Studies, in the laboratories of the present authors, have shown that photoaldrin (PA), photodieldrin (PD), and photoheptachlor (PH) are several times more toxic to houseflies, aquatic insects, crustacea, other aquatic tPresent address: College
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