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The oxidation of DHE yields two fluorescent products: 2 hydroxyethidium EOH , which is more specific for superoxide; and, the unspecific ethidium. The method is complicated by the fact. The endoplasmic reticulum, which provides the environment for protein folding is also another main source of ROS production. The ROS generated from the ER mainly come from oxidative protein folding especially during disulphide bond formation Tu and Weissman Two electrons are transferred to the protein disulphide isomerase Pdi1p, then to the flavoprotein-containing Ero1p during this process and under aerobic conditions, oxygen acts as the terminal electron acceptor with the probable generation of hydrogen peroxide Tu et al.

In addition, ER stress caused by conditions such as hypoxia and viral infection, which disrupts ER homeostasis, also produce ROS including superoxide Tan et al. H2 O2 , another ROS, is generated from the breakdown of O 2 by superoxide dismutases SODs and from oxidases and -oxidation of fatty acids in peroxisomes. The hypochlorite produced from H2 O2 by the action of myeloperoxidase in neutrophils during phagocytosis can act on free amines to form chloramines, which are also toxic to cells.

The most dangerous ROS is the highly reactive hydroxyl radical, OH, which reacts indiscriminately with most cellular constituents Beckman et al. Therefore the mechanisms involved in metal ion homeostasis for Cu and Fe ions play important role in cellular defences by minimizing formation of ROS. In plants, both mitochondrion and chloroplast can be the source of ROS production and of these the chloroplast may be more active.

Fungal metabolites and air pollutants can generate singlet oxygen 1 O2 in the presence of light Scandalios In plants, singlet oxygen is produced by photo-excited chlorophyll and can cause membrane lipid peroxidation, photo-oxidation of amino acids and DNA damage. Peroxynitrite is very reactive and its reactions eventually enhance formation of radicals such as nitrogen dioxide NO2 and the carbonate radical CO 3 Fig.

These reactive species can nitrate aromatic amino acid residues Beckman et al. At the outset it should be understood that there is no such thing as a single oxidative stress. Rather there are different forms of oxidative stress that arise depending on the ROS that is being generated in the cell. This became clear from the results of screening of the effects. RH indicates a compound that can accept an electron to become a radical. In analysis of the roles of ROS and RNS in processes such as ageing it is therefore important to identify which species is involved, and not rely on the use of a single oxidant such as hydrogen peroxide as a general oxidant.

Reactions between these reactive species and cellular components produce many secondary ROS and other radicals. Their reactivity varies significantly. Damage to. Treatment with paraquat which generates O 2 and H2 O2 can also lead to intrachromosomal recombination and significant levels of interchromosomal recombination at high doses Brennan et al. While DNA damage may be a contributor to cell death, it might not be a main one, since mutants that are affected in DNA repair do not feature strongly in the set of mutants that are sensitive to a range of different ROS-generating reagents Thorpe et al.

Moreover there is considerable overlap or redundancy in cellular antioxidant functions, and it requires deletion of all five peroxiredoxin genes involved in detoxification of hydroperoxides to generate strains with greatly increased mutation rates Wong et al. Protein damage caused by OH leads to cross-linking, fragmentation and oxidation of amino acyl residues, particularly aromatic side chains and cysteine Stadtman The protein hydroperoxides formed are reactive and upon decomposition release free radicals leading to further protein modification and unfolding Gebicki et al.

Damage to amino acids leads to formation of hydroxylated derivatives and oxidation of aromatic amino acid residues can produce reactive phenoxy radicals Aeschbach et al. FeS-proteins are very susceptible to O 2 , as evidenced by the methionine and lysine auxotrophy of the double sod1 sod2 mutant lacking superoxide dismutase SOD activity Liu et al. Hydrogen peroxide also leads to reversible oxidation of reactive cysteine residues in some proteins to form disulphides or sulfenic acid residues, or irreversible oxidation to sulphinic or sulphonic acids.

In the presence of reactive nitrogen species there can be S-nitrosylation as well. Some proteins that have oxidised cysteine residues have been identified in cells exposed to H2 O2. In addition, a number of stress chaperones, enzymes involved in carbohydrate, energy and amino acid metabolism, proteins involved in translation and proteolytic degradation were susceptible to cysteine oxidation.

Many of the same proteins can undergo reversible disulphide formation with glutathione glutathionylation as a protective measure Grant et al. Unsaturated fatty acyl groups are the most susceptible to OH and the protonated form of O 2 , can initiate autocatalytic lipid peroxidation to form reactive lipid radicals and lipid hydroperoxides Gunstone Fig. Lipid hydroperoxides are among the most toxic hydroperoxides to yeast cells Alic et al.

1. Introduction

These toxic molecules can cause significant damage to cell membranes Evans et al. When lipid peroxides are broken down, they can produce reactive aldehydes such as malondialdehyde and in organisms with multiply unsaturated fatty acids not Saccharomyces cerevisiae 4-hydroxynonenal, which can contribute to the carbonylation of proteins Esterbauer et al. As discussed in subsequent chapters, carbonylation has also been implicated in protein. Proteins that are vulnerable to carbonylation following exposure of cells to H2 O2 include glyceraldehydephosphate dehydrogenase isozymes, aconitase, pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, Hsp60p, fatty acid synthase and Cu-Zn SOD Costa et al.

Cellular Defences The recent rapid development in genomic technologies has provided advanced tools including deletion mutants for every non-essential gene Winzeler et al. The use of these approaches has led to a much more detailed insight into how cells respond to ROS and other stresses. Aerobic organisms are constantly exposed to many different ROS and their toxic products generated from both endogenous and exogenous sources.

For some ROS such as O 2 and H2 O2 there is some understanding that they may act as signaling molecules at low concentration. At higher concentrations these are generally very detrimental to cells. Therefore organisms have evolved a very wide range of both enzymatic and non-enzymatic cellular defence mechanisms against the deleterious effects of ROS. These include constitutive redox protection systems buffering the cell against sudden exposure to oxidants as well as inducible systems that include modulation of gene expression and metabolism to up-regulate antioxidant and repair systems and down-regulate growth functions to allow the cells time to repair damage Dawes ; Gasch et al.

Non-enzymatic Defence Systems The non-enzymatic antioxidant functions include low molecular mass redox-active molecules such as glutathione, D-erythroascorbate the 5-carbon analogue of ascorbate and ubiquinol. The water-soluble tripeptide glutathione GSH; -glutamylcysteinyl-glycine is the most abundant low molecular mass thiol in yeast cells. It can be oxidised to form the disulphide GSSG by a range of oxidants, including H2 O2 and disulphides, and hence GSH makes up a substantial proportion of the cellular redox buffering capacity protein thiols also constitute a fairly high proportion of the redox buffering capacity.

GSH has a range of functions in addition to its many roles in protecting against oxidative stress; these include protein folding, amino acid transport and metabolism and secretion of various xenobiotic compounds Dawes The rate of reaction of H2 O2 with GSH is slow relative to that with some of the enzymatic defence systems, especially the peroxiredoxins if the yeast enzymes have similar activity to their mammalian homologues Peskin et al.

The main antioxidant activity of GSH probably arises from its role in maintenance of cellular. Saccharomyces cerevisiae does not synthesise significant amounts of L-ascorbate, which in other organisms has a strong antioxidant activity as a scavenger of free radical species including superoxide anion, lipid peroxy radicals and the hydroxyl radical.

On the other hand S. Yeast also lacks tocopherols found in higher eukaryotes, and a likely contender for the main lipid-soluble antioxidant is ubiquinol coenzyme Q the yeast version has a side chain with six isoprenoid residues rather than the ten found in humans. Mutation of any of the genes in the coenzyme Q biosynthetic pathway leads to the respiratory petite phenotype as expected for a disruption of respiration.

The coq3 mutant is very sensitive to polyunsaturated fatty acids compared to the wild type, and since the sensitivity is rescued by the addition of antioxidants reacting with free radicals it has been suggested that ubiquinol does play a role in protection against the products of lipid autoxidation Bossie and Martin Enzymatic Defences The wide range of ROS generated in cells has led to evolution of a large number of enzymes to detoxify the ROS or repair the damage caused by them, and the role of these enzymes and their regulation have previously been reviewed extensively Dawes Many of those that have been identified to date are listed in Table 2.

These enzymes are localised to various cellular compartments and hence the cells have different strategies for removal of ROS or repair that are specific to different compartments. Some of the different mechanisms for dealing with the main ROS species and their damage are summarised for the cytoplasm Fig. There is no enzyme known that can detoxify the hydroxyl radical, which reacts very rapidly with the nearest molecule and is therefore unlikely to accumulate in cells. The superoxide radical anion is removed by dismutation to hydrogen peroxide and oxygen catalysed by superoxide dismutases SODs.

The less abundant Mn-containing Sod2p is found in the mitochondrial matrix Gralla and Kosman Table 2. Function Nuclear thiol peroxidase Mitochondrial peroxiredoxin with thioredoxin peroxidase activity Cytoplasmic thioredoxin peroxiredoxin Cytoplasmic thioredoxin peroxiredoxin Cytoplasmic thioredoxin peroxiredoxin. Basic leucine zipper bZIP transcription factor Nuclear response regulator and transcription factor Transcriptional activator related to Msn4p Transcriptional activator related to Msn2p.

Cytosolic and mitochondrial glutathione oxidoreductase Gamma glutamylcysteine synthetase catalyzes the first step in glutathione biosynthesis Glutathione synthetase; catalyzes the second step in glutathione biosynthesis Phospholipid hydroperoxide glutathione peroxidase Phospholipid hydroperoxide glutathione peroxidase Phospholipid hydroperoxide glutathione peroxidase Cytoplasmic di-thiol glutaredoxin Cytoplasmic di-thiol glutaredoxin Nuclear shuttling monothiol glutaredoxin Nuclear shuttling monothiol glutaredoxin Mitochondrial monothiol glutaredoxin; required for iron-sulfur cluster biogenesis Cis-golgi localized monothiol glutaredoxin Cis-golgi localized monothiol glutaredoxin Glutaredoxin; localizes to the cytoplasm Proton-coupled oligopeptide transporter of the plasma membrane; transports glutathione Endoplasmic reticulum-associated glutathione-S-transferase Glutathione-S-transferase possibly mitochondrial.

Cytoplasmic thioredoxin reductase Mitochondrial thioredoxin reductase Cytoplasmic thioredoxin Cytoplasmic thioredoxin Mitochondrial thioredoxin. Cytosolic catalase T Peroxisomal catalase A Cytosolic copper-zinc superoxide dismutase Mitochondrial manganese superoxide dismutase Mitochondrial intermembrane space localised Cytochrome C peroxidase. Mutants lacking Sod1p are viable, but have reduced growth rates under aerobic conditions.

The double sod1 sod2 mutant grows slowly in air, requires methionine and lysine for growth and has an increased mutation rate Liu et al. There is a wide range of enzymes capable of detoxifying hydroperoxides. Catalases are reportedly specific to H2 O2 and unable to accommodate larger hydroperoxides in their catalytic sites Dawes Saccharomyces cerevisiae has. The main reactive oxygen species include the superoxide anion radical and hydrogen peroxide and organic peroxides ROOH that are detoxified to water via the Cu,Zn-superoxide dismutase, catalase or glutathione systems.

Oxidised thioredoxins are reduced directly by thioredoxin reductases using electrons supplied by NADPH. Yeast genes are denoted in bold and italic uppercase and the protein product of the gene is designated by Roman type, with the first letter capitalized and suffix p. The cytosolic catalase T encoded by CTT1 is inducible by oxygen, heat, osmotic and oxidative stress, copper ions and availability of several nutrients Bissinger et al. The peroxisomal catalase encoded by CTA1 is induced by oxygen, growth on respiratory substrates and fatty acids, and is repressed by glucose Ruis and Hamilton While disruption of CTT1 has been reported to lead to sensitivity to H2 O2 , disruption of either or both catalase genes did not.

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Yeast genes that encode the enzymes are in bold italics. During stationary phase the double mutant is more sensitive to H2 O2 than the wild-type Izawa et al. Comparison of the sensitivity of mutants affected in the catalases and in glutathione metabolism has shown that in exponentially growing cells glutathione has a more important role than the catalases in responding to H2 O2 Grant et al. This is consistent with the long-held view that in mammalian cells the glutathione peroxidases have a greater role in detoxification of H2 O2.

In fact, kinetic data for purified enzymes would indicate that where the peroxiredoxins discussed below are present in a cellular compartment, they would have a more important role than either the glutathione peroxidases or catalases in breaking down H2 O2.

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The peroxiredoxins use thioredoxin as the reduced substrate rather than glutathione Peskin et al. These enzymes have a role in repair as well as detoxification since many have the ability to repair damage to proteins that have oxidised thiols as indicated in Fig. Yeast cells have three glutathione peroxidases Gpx encoded by GPX Question marks denote as yet unidentified enzymes.

Yeast genes encoding the enzymes are in bold italics. Of the deletants, only the gpx3 mutant is sensitive to peroxides, which is probably due to the fact that the enzyme is also the sensor of H2 O2 damage in cells Delaunay et al. The thioredoxin peroxidases peroxiredoxins are a family of cysteine-dependent peroxidases that react rapidly with H2 O2 and other alkyl hydroperoxides, including amino acid hydroperoxides and peroxy residues in oxidised proteins, and in mammalian systems the peroxiredoxins may be the most relevant anti-oxidant systems for removing hydrogen peroxide under normal conditions Peskin et al.

All peroxiredoxins contain a conserved peroxidatic cysteine residue in the active site, which is oxidised to a sulfenic acid residue by the hydroperoxide. In 2-Cys enzymes this sulfenic acid residue initially reacts with another cysteine residue to form an intra-molecular disulfide bridge, which forms a substrate for subsequent reduction by the thioredoxin system Fig.

In 1-Cys peroxiredoxins lacking the second conserved cysteine there is an alternative reduction system for the yeast mitochondrial Prx1p this reduction is mediated via glutathionylation of the catalytic cysteine residue and subsequent reduction by glutathione catalysed surprisingly by the mitochondrial thioredoxin reductase, Trr2p Greetham and Grant Tsa1p is a cytoplasmic and ribosomeassociated 2-Cys enzyme, and in addition to its peroxidase activity, under oxidative stress it can self-associate to form a high molecular mass complex with chaperone activity, which can also contribute to repair of protein damage Trotter et al.

Tsa2p and Ahp1p are also located in the cytoplasm; in its active form Ahp1p is covalently attached to the ubiquitin-related protein Urm1p Goehring et al. Deletion of either TSA1 or TSA2 leads to some hypersensitivity to hydrogen peroxide and nitrosative stress and the tsa1 tsa2 double mutant is even more sensitive Wong et al.

DOT5 encodes a 2-Cys peroxiredoxin that is located in the nucleus. The enzyme is more active against alkyl hydroperoxides, is induced on respiratory substrates and is required for starvation survival Cha et al. Interestingly, deletion of all five peroxiredoxins does not lead to loss of viability. The multiple deletant grows slowly, has induced levels of other antioxidant enzymes and has a significantly increased rate of mutation Wong et al.

The mitochondrion lacks catalase, and in addition to be the source of a relatively large proportion of the O 2 generated in cells, it is also the site of assembly of the very oxidant sensitive FeS complexes. The antioxidant functions in the mitochondrion are augmented by the cytochrome c peroxidase, which is located in the mitochondrial inter-membrane space and encoded in the nucleus by the CCP1 gene.

Deletion of this gene does not affect viability of cells under aerobic conditions, even on respiratory substrates, but leads to increased sensitivity to H2 O2 but not to paraquat and formation of petites on respiratory substrates Jiang and English It has been suggested that Ccp1p has a role in signaling oxidative stress via the Skn7p transcription factor Charizanis et al.

A recent report has shown that the glutathione transferases Gtt1p and Gtt2p are also important for protecting the cells against H2 O2 stress by reducing formation of lipid peroxides as well as products of protein carbonylation Mariani et al. The above discussion is mainly concerned with removal of ROS or their toxic products. There are, however, repair functions, which can remove the damage from molecules. Alkyl hydroperoxides formed from lipids or proteins are reduced by the peroxiredoxins, and the peroxidases forming the corresponding alcohol, which is usually less toxic.

One class of damage that is important is that caused to reactive protein thiol groups, which are among the most readily oxidised residues in proteins. Reactive cysteinyl residues can be oxidised to disulphides via two protein. This does not require enzymatic action, and can serve a protective function by preventing further irreversible oxidation of the thiol group. In most cases cysteine oxidation to the sulfenic acid can be reversible through the action of a number of enzymes especially the thioredoxins and glutaredoxins , while the subsequent oxidation to sulfinic or sulfonic acids is not.

One exception is the sulphiredoxin enzyme encoded in S. The cell has two classes of low molecular mass proteins with thiols at the reactive site that play many roles in the cell, not least the repair of oxidatively damaged thiols in proteins, as well as in maintenance of cellular reducing potential. These are the thioredoxins and glutaredoxins, which show structural similarity and which share a number of functions.

Both proteins can exist in the reduced or oxidised forms. Both thioredoxin and glutaredoxin are also directly involved in nucleic acid biosynthesis as the hydrogen donors to ribonucleotide reductase, and in sulphur metabolism Trotter and Grant In yeast there are three thioredoxins two Trx1p and Trx2p are located in the cytoplasm Gan and Trx3p in the mitochondrial matrix Pedrajas et al.

The cytoplasmic redoxin system is not essential for growth, since the triple mutant trx1 trx2 trr1 can grow, although the double trx1 trx2 mutant is affected in cell cycle progression and requires cysteine and methionine due to loss of the reducing power for sulphate assimilation Muller The TRX2 gene is regulated by the Yap1p transcription factor and its activity is important for the inactivation of Yap1p as the cell recovers from H2 O2 stress see later discussion of Yap1p this chapter.

The trx2 deletion mutant has increased sensitivity to hydroperoxides during stationary phase Garrido and Grant Deletion of both thioredoxins 1 and 2 led to the greatest shift in cellular reducing potential of any of the antioxidant mutants tested in exponential phase, and deletion of thioredoxin reductase 1 had the same effect in stationary phase Drakulic et al. Glutaredoxins are heat-stable glutathione-dependent disulphide oxidoreductases Holmgren and Aslunf , which have some overlap in their function with the thioredoxins, including the ability to donate hydrogen to ribonucleotide reductase.

The importance of the glutaredoxins in repair of ROS damage is due to their ability to catalyse the cleavage of mixed disulphides between GSH and proteins Chrestensen et al. Grx1p and Grx2p. The three monothiol glutaredoxins, Grxp, have only one cysteine at the catalytic site. Grx1p and Grx2p have glutathione peroxidase activity in addition to thiol transferase activity Collinson et al. Grx1p is located in the cytoplasm, Grx2p has two isoforms, one cytoplasmic and the other mitochondrial Pedrajas et al. All combinations of the trx1, trx2, grx1 and grx2 mutations are viable except the quadruple mutant lacking any of the cytoplasmic thioredoxins and glutaredoxins Trotter and Grant indicating the strong overlap in the essential functions of glutaredoxins and thioredoxins.

Deletion of GRX5 leads to sensitivity to oxidative stress. Grx3p and Grx4p are located in the nucleus and have been shown to be important for the iron inhibition of the transcription of the Aft1p transcription factor regulating iron homeostasis in S. A critical component of many oxidative damage repair and detoxification systems is the generation of NADPH to provide reducing equivalents.

Additional proteins such as heat shock proteins Kalmar and Greensmith and DNA damage repair enzymes Salmon et al. Cellular Responses to ROS Physiological management of oxidative stress situations includes metabolic readjustments, which occur within a very short time seconds to minutes and represent non-genomic consequences of the oxidative stress Gruning et al. On a somewhat longer time scale, the transcriptome of the stressed cells changes and responds by activating the antioxidant defence pathways and, at higher doses, the cell death pathway of yeast Gasch et al.

Yeast cells respond to oxidative stress in dose-dependent manner. At low doses below the level at which cell death occurs, the cells adapt to become more resistant to a subsequent dose that would otherwise be lethal and also to some other oxidants Collinson and Dawes ; Evans et al. At higher doses, the cells delay cell division Alic et al. In the presence of very high doses, the cells initiate apoptosis Madeo et al.

This adaptation is observed in both human cells Kim et al. The adaptive response elicited by a particular ROS can in some cases confer increased resistance to another form of ROS. Heat stress causes oxidative stress Davidson et al. By contrast, pre-treatment with low doses of H2 O2 does not confer thermotolerance Collinson and Dawes Previously it was reported that pretreatment with H2 O2 leads to superoxide tolerance but not vice versa Flattery-OBrien et al.

Although the latter are conflicting results, it is clear that cross-adaptation can occur and there is hierarchy with regards to this process. The cross-adaptation could be a result of the generation of secondary ROS during pre-treatment with some oxidants to the concentration that can elicit an adaptive or a damage response. Although physiological adaptation to oxidative stress was discovered relatively early, the mechanisms involved in adaptation to specific ROS are not fully understood.

Different ROS produce distinct adaptive responses, which require de novo gene expression and protein synthesis, and the responses are transient lasting for about 1. Genes involved in the adaptive response were predicted to be a subset of those that are induced in the acute response Costa and Moradas-Ferreira At low adaptive doses there is an up-regulation of metabolic systems for synthesis of NADPH and export of LoaOOH from the cell and a mild down-regulation of protein synthesis gene expression, but somewhat surprisingly there is a downregulation of the genes encoding more general oxidant defence enzymes including those for thioredoxin 2 and glutaredoxin 1.

Induction of these more general oxidative and general stress response genes did not occur until the maximal adaptive dose was reached Alic et al. This led to the speculation that the major antioxidant enzymes are not induced until there is a threshold dose, which may be that which overcomes the redox buffering capacity of the cell. During LoaOOH adaptation, transcription is regulated in part by Pdr1p or Pdr3p, which are two homologues transcription factors that recognize the pleiotropic drug-resistance elements controlling the synthesis of multidrug resistance transporters. Genome wide analysis of the set of deletion mutants identified mutants that are sensitive to H2 O2 Thorpe et al.

Further sub-screening of those mutants sensitive to H2 O2 identified seven genes that when deleted led to a marked reduction in the adaptive response to H2 O2 Ng et al. These genes can be divided into two categories: i genes encoding transcription factors such as Yap1p one of eight yeast homologues of the human AP-1 family of proteins , which is the major oxidative stress transcription factor in yeast, Skn7p which partners Yap1p to regulate genes encoding antioxidant enzymes and the more general transcription co-activator Gal11p; and, ii genes that are involved in the generation of NADPH via either the pentose phosphate pathway or in the mitochondrion.

Similar adaptation to H2 O2 also occurs when anaerobically grown cells are exposed to oxygen for a short time Beckhouse et al. Although inhibition of glutathione metabolism has been reported to reduce adaptation, we have not found loss of adaptation in the mutants that are unable to synthesise glutathione. Yap1p and Yap2p were shown to play a role in adaptation to H2 O2 but not to O 2 in a previous study Stephen et al. The critical role of Yap1p and of NADPH generation systems could indicate that adaptation is due to mainly to activation of Yap1p, and that it is maintained in the cell as long as Yap1p remains activated after an initial oxidative insult.

This period can last up to 1. Most recently, a combination of genetic screening of the S. These two transcription factors were found to respond earlier than the known oxidative response transcription factors. Yap1p and Skn7p and regulate targets involved in ergosterol metabolism, zinc homeostasis and fatty acid metabolism. The discovery of the role of these additional transcription factors supports the suggestion that membrane integrity is increased as part of the adaptation to H2 O2 Branco et al.

Cell Cycle Arrest Cell cycle delay or arrest upon exposure to ROS occurs, possibly to allow the cells to repair damage that would otherwise be deleterious to cell survival. Progression through the cell cycle is regulated by coordinated gene expression under the control of a small number of transcription regulators which are sequentially activated Burhans and Heintz The response is through stress signalling and inhibition of gene expression that is required for cell cycle progression Burhans and Heintz However, the superoxide generators, paraquat and menadione, as well as exposure to hyperbaric oxygen, cause a pronounced G1 arrest independent of Rad9p Flattery-OBrien and Dawes The differential effect of H2 O2 and menadione on cell cycle delay results from expression of two small co-expressed groups of genes that are under the control of the transcription complexes Mcm1-Fkh2-Ndd1 Shapira et al.

This shows similarity to the oxidative stress response in mammalian cells Kops et al. The expression of cyclins and activation of cyclin-dependent kinases CDK are important for the transitions from one phase to another during cell division Burhans and Heintz The sod1 mutant grows slowly due to an increased time spent in the G1 phase of the cell cycle and in the presence of excess oxygen they arrest in G1 phase resulting from inhibition of transcription of CLN1 and CLN2 genes encoding the auto-regulated cyclins involved in progression to S phase Lee et al.

The products of lipid peroxidation including 4-hydroxynonenal Wonisch et al. Screening of LoaOOHsensitive strains from the genome-wide deletion collection identified 47 deletants that were unable to cause cell cycle delay upon treatment with LoaOOH Alic et al. One of the interesting deletants that did not undergo cell cycle delay in response to LoaOOH lacked Swi6p.

While Swi6p regulates cell-cycle arrest following DNA-damage through phosphorylation by Rad53p Sidorova and Breeden , its involvement in regulating cell-cycle arrest in response to oxidative stress is not dependent on the DNA-repair pathway Flattery-OBrien and Dawes Instead Swi6p regulates cell-cycle delay by functioning as a sensor and transducer. Mutation of the reactive cysteine residue to an alanine abolishes the cell cycle delay caused by the oxidant, but not cell cycle progression.

This leads to altered transcription of the cyclin genes that are required for triggering of S phase Chiu et al. Based on microarray data, the heat shock response and glucose transport are also involved in Swi6p-dependent cell cycle delay Fong et al. Additionally, three homologous genes, two of which OCA1 and SWI4 encode putative protein phosphatases, may also be involved in stress signaling and cell cycle progression upon treatment with LoaOOH Alic et al.

Transcriptional Regulation Adaptation and the subsequent repair mechanisms require regulation of gene expression. Many repair and antioxidant defence systems including catalases, SODs and enzymes involved in glutathione metabolism, thioredoxins and glutaredoxins are found to be up-regulated following exposure to ROS. Genome-wide transcriptional analysis has shown that several hundred genes are either induced or repressed on exposure of cells to moderate to high environmental stresses including heat, several ROS, starvation, osmotic and salt stress Causton et al. Although no two stress conditions lead to an identical pattern of gene expression, a very large group of genes were found to respond similarly and transiently across most of the stresses.

This common response has been known as either an environmental stress response ESR or a common environmental response. The common response genes include those involved in carbohydrate metabolism, breakdown of ROS, cellular redox control, heat-shock proteins, protein degradation, lipid metabolism, cell wall modeling, vacuolar functions, autophagy and signaling pathways.

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Many are also regulated by the protein kinase C PKC pathway, which is involved in signalling cell integrity Gasch et al. In addition it was proposed that the response to stresses including ROS may involve the induction of genes that are associated with changes in either cell wall or membrane permeability or loss of protein integrity, which might require up-regulation of pathways that supply energy for ATP-dependent processes such as the activity of molecular chaperones heat shock proteins in assisting protein folding Causton et al.

In addition to the genes of the ESR, there are others that are either induced or repressed by oxidative stress and specifically by a particular ROS Alic et al. Tucker and Fields Only 12 mutants were sensitive to all the compounds tested whereas many of the rest of the mutants were sensitive to a single oxidant. This shows that the responses are very dependent on the nature of the oxidant. Deletion of the genes involved in mitochondrial functions as affecting the synthesis or assembly of components of the respiratory chain in particular complexes III and IV and protein synthesis mitochondrial ribosomal subunits leads to sensitivity in mainly to H2 O2.

The mutants that are sensitive to menadione include those affected in the pentose phosphate pathway indicating the importance of NADPH or of antioxidant functions that require NADPH in the detoxification of O 2. Therefore no single oxidant represents general oxidative stress. The genes identified from deletant studies on the sensitivity to a particular ROS shows little correlation with those whose transcripts are altered following treatment with the same ROS Alic et al.

This shows that deletant studies identify constitutive functions that are required before exposure to ROS to increase survival while transcription studies shows those that are likely to be concerned with either repair or removal of damage. One important defence mechanism against oxidative stress is maintenance of the cellular redox environment. These molecules play different roles in buffering cellular redox potential.

Of them, the thiol-containing tripeptide glutathione is the most important. Disruption of glutathione homeostasis, particularly depletion of glutathione leads to serious consequences for ROS production, cell degeneration, ageing and apoptosis Fernandes and Holmgren ; Holmgren Early work from a number of groups analysing the promoters of many of the genes encoding anti-oxidant enzymes indicated that the response to ROS was mediated by a set of transcription factors, including: the relatively specific oxidative stress-response factor, Yap1p Moye-Rowley et al.

As discussed earlier, in addition to the antioxidant defence systems, the roles of copper ion homeostasis and ion uptake regulated by Ace1p Carri et al. The responses of individual antioxidant genes are rarely under the control of a single transcription factor. Each gene has its own mixture of promoter. Two sets of genes were identified in the H2 O2 stimulon by proteomic analysis Godon et al.

One set of genes, including those involved in many of the cellular antioxidant processes, requires Yap1p in conjunction with the auxiliary transcription factor Skn7p while the others, such as those needed for NADPH synthesis, only depend on Yap1p. Cell cycle delay and induction of antioxidant genes are observed only at high doses Alic et al. Since aerobic cells are constantly exposed to low concentrations of lipid peroxides, it is may be advantageous to repair the damage caused by low doses without impairing the capacity of the cell to replicate.

The response of gene expression to ROS is controlled not only at the level of transcription but also by the dynamics of mRNA decay. Systematic analysis on a genomic scale of the changes in rate of transcription and mRNA concentration for individual genes using genomic run-on methodology has indicated that changes in mRNA decay rates are as important as those in transcription rate during adaptation to oxidative stress Molina-Navarro et al.

Translational Control Inhibition of protein synthesis occurs following most stresses, and this is true after most forms of ROS stress with a decrease in transcription of many genes involved in the protein synthesis machinery Gasch et al. However, recent elegant work from the Grant laboratory has shown that in Saccharomyces cerevisiae the rate of protein synthesis decreases rapidly after treatment of cells with H2 O2 Shenton et al.

Some of this inhibition occurs at the level of translation initiation, and is dependent on the Gcn2p protein kinase, which phosphorylates the subunit of the eukaryotic initiation factor eIF2. There appears to be another component of the decreased rate of protein synthesis that is Gcn2p-independent since there was still some inhibition in a gcn2 mutant. The data from polysome analysis were consistent with this inhibitory effect occurring at either the elongation or termination step of translation.

Microarray analysis of monosome- and polysomebound mRNA showed that a particular set of mRNAs were preferentially bound to ribosomes following stress, and these included mRNAs for stress protective molecules such as thioredoxin reductase 1 Trr1p and superoxide dismutase.

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These experiments were extended to show that the Gcn4p transcription factor mediating the general control of amino acid biosynthesis response is translationally up-regulated by H2 O2 and that Gcn4p is required for hydroperoxide resistance, indicating that there is an overlap of this regulatory system into the domain of transcription. Similar responses have also been observed after treatment of cells with other oxidants including cumene hydroperoxide, diamide and cadmium Mascarenhas et al.

In addition to the Gcn2p-dependent response, the eIF4Ebinding protein Eap1p is also required for regulation of translation initiation during cadmium and diamide stress. Based on the analysis on the genes whose expression is altered by H2 O2 , it is clear that extensive metabolic reconfiguration is needed for optimal survival of oxidative stress. Apoptosis Here we provide a short overview of the role of ROS in apoptosis, for a more extensive treatment of the relation of apoptosis with yeast aging the reader is referred to Laun et al. Chapter 10, this volume.

At high doses of oxidants, cells initiate cell death by a form of apoptosis and at extreme doses by necrosis Teramoto et al. Apoptosis was first observed in a cdc48 mutant that lacks an essential gene involved in the translocation of ubiquitinylated proteins from the ER to the proteasome for degradation Madeo et al. The process is characterised by the flipping of phosphatidylserine from the inner to outer layer of the cell membrane, chromatin condensation, accumulation of DNA strand breaks, nuclear fragmentation and formation of apoptotic bodies. Subsequently, apoptosis was also found in the gsh1 mutant lacking the ability to synthesise glutathione and in cells exposed to other ROS including H2 O2 Madeo et al.

Moreover, elevated levels of ROS are found in the cells undergoing apoptosis triggered by other conditions such as NaCl stress Wadskog et al. Yeast has a caspase-like protein although not one with an aspartyl residue at its active site like the mammalian caspases encoded by the YCA1 gene, a caspase regulating serine protease Madeo et al. The involvement of Yca1p in apoptosis is not well understood. Over-expression of Aif1p in yeast promotes apoptosis in the presence of an apoptotic level of H2 O2 Wissing et al.

The exact mechanism of how apoptosis is initiated by ROS still needs to be carefully investigated. As mentioned earlier, no one oxidant is representative of a general oxidant and therefore further careful analysis is needed on what damage is caused by each oxidant and how the cells respond to it. Other Cellular Responses In addition to the responses described above, recent studies have identified other unique cellular mechanisms that form part of the cellular responses to oxidative stresses.

One such mechanism involves post-translational changes rerouting flux through metabolic pathways to promote survival Ralser et al. During this process a number of enzymes are modified causing rapid and reversible changes in their enzymatic activity Biswas et al. Tdh3p, but not Tdh2p is a major target of glutathionylation following treatment with H2 O2 , which reduces the activity of both enzymes. However, only Tdh3p activity is restored after a recovery period indicating that the glutathionylation is reversible and protects the enzyme.

The tdh3 deletion mutant is very sensitive to a lethal dose of H2 O2 , indicating that glutathionylation of Tdh3p is required for survival during conditions of oxidative stress. In contrast, the non-thiolated Tdh2p is required during chronic exposure to a low level of oxidants under conditions in which the Tdh3p would be S-thiolated and inactive Grant et al.

Overexpression of Rny1p also promotes cell death even in unstressed cells. The other interesting observation is the induction of prion formation at higher frequency under stressful conditions including treatment with H2 O2 Tyedmers et al. This phenotype is heritable if it provides advantage to cell survival. Sensing Stress Although many transcription factors involved in stress responses are identified, how oxidants are sensed and the signals are transmitted are not yet fully understood. The most well studied mechanism is the role of cysteine residues and disulphide bonds in redox sensing seen with the mechanism whereby the Yap1p transcription factor is activated.

Yap1p In yeast, Yap1p regulates many key antioxidant genes Gasch et al. Under unstressed conditions, Yap1p interacts with the nuclear exportin Crm1p through the nuclear export signal NES in the C-terminal domain of Yap1p and is exported out of the nucleus Kuge et al. A mutation that affects the C-terminal region of Yap1p and causes constitutive nuclear localisation of Yap1p does not lead to increased tolerance to H2 O2 Coleman et al. This indicated that in addition to sub-cellular localisation, the nature of disulphide bonds formed in the cysteine-rich regions of Yap1p also affects the expression of Yap1-targeted genes possibly through the changes in the binding affinity for the promoters of the genes that are involved in tolerance to a particular stress.

In vivo analyses have indicated that inactivation of Yap1p to its reduced state is most likely effected by thioredoxin Carmel-Harel et al. Since Yap1p controls the synthesis of thioredoxin 2 Kuge and Jones and thioredoxin reductase Lee et al. Although the presence of H2 O2 leads to changes in Yap1p, H2 O2 is directly sensed by the peroxiredoxin Gpx3p through a cysteine residue C36 Delaunay et al. H2 O2 converts this residue to a sulfenic acid, which then reacts with Yap1p to form an intermolecular disulphide bond between C36 of Gpx3p and C of Yap1p.

The disulphide exchange reaction that follows leads to the formation of a CC disulphide bond in Yap1p and regenerates reduced Gpx3p. Gpx3p-dependent responses to oxidative stress involve induction not only of Yap1p-dependent antioxidant defence genes but also other proteins participate in various cellular mechanisms such as biogenesis of cellular components, cell cycle and energy metabolism which are independent of Yap1p.

These compounds activate Yap1p through modification of the C-terminal residues that are different to those affected by H2 O2. Swi6p As described under the above section on cell cycle delay, the transcription factor Swi6p has recently been shown to be involved not only as a transducer, but also as a sensor, in an oxidative stress response that coordinates oxidative stress sensing with. Deletion of this gene abolishes cell cycle delay induced by LoaOOH, and as in the above system the initial event is oxidation of a reactive cysteine C residue to a sulfenic acid.

Skn7p About one half of the genes, including those encoding major antioxidant functions such a TRX2, TRR1, GPX2 and CCP1, that are activated by oxidative stresses under the control of Yap1p also require the cooperation of the second transcription factor Skn7p, which plays a similar cooperative role in some other stress responses He and Fassler ; Lee et al. Unlike the cysteine-based redox sensor Yap1p, none of the cysteines in the receiver domain of Skn7 are required for the oxidative stress response; instead Skn7 is phosphorylated following exposure to oxidation He et al.

This oxidant-dependent phosphorylation is abolished in the absence of Yap1p. Skn7 is constitutively nuclear, and its association with Yap1p to form a complex is also important for the Skn7p response to oxidants. Therefore the authors proposed that the association of Yap1p with Skn7p in the nucleus is a prerequisite for Skn7p phosphorylation and activation of oxidative stress response genes. Under stress conditions, they are imported into the nucleus and the nuclear export is dependent on the Msn5p nuclear export factor Durchschlag et al. Heterogeneity In addition to the genotype of the cells, the phenotypic heterogeneity that is evident among individual cells within isogenic cultures is also important for cellular responses to oxidative stress Sumner and Avery For examples, treatment with a high dose of oxidant does not lead to complete inviability, but instead a.

This differential stress sensitivity is driven by non-genetic heterogeneity, which could result from differences in cell cycle progression, cell age, mitochondrial activity, ultradian rhythms metabolic oscillations , epigenetic regulation and stochastic variation. These aspects have been reviewed in detail Sumner and Avery The variability in copper resistance has been observed in individual cells and has been related to the cell cycle and age-dependent regulation of Cu, Zn-superoxide dismutase Sod1p Sumner et al.

Similarly, the heterogeneity in GSH content within the cell population leads to differing stress resistance to cadmium and H2 O2 Smith et al. Metabolic oscillations and heterogeneity in GSH content can be suppressed by over-expression of Gts1p, and this decreases variation in stress resistance. Oxidative Effects and Ageing Owing to the long lifespan, ageing studies in mammals are mostly performed in human or mouse fibroblasts culture.

But the relevance of the findings in the cell culture to the organismal ageing process is still debatable Campisi and dAdda di Fagagna As a second approach, organisms which age rapidly and can be manipulated easily both genetically and environmentally are used for ageing research. These include fruit flies Helfand and Rogina and worms Houthoofd and Vanfleteren ; Olsen et al. The single celled eukaryotic S. The former also known as mother cell-specific ageing is defined as the number of times each cell can divide before senescence and the latter studies how long the yeast cell can remain viable in the non-dividing post-mitotic state under nutrient-depleted conditions.

Since Harman proposed the free-radical theory of ageing, which states that ageing is caused by accumulation of macromolecular damage caused by free radicals Harman , researchers have been trying to find the link between the build up of ROS and the ageing process. In agreement with Harmans theory, ROS production from mitochondria, as well as biochemical markers of oxidative damage, are found to be elevated with age Aguilaniu et al. These observations are true from yeast, to mice and human cells. Some conditions that increase intracellular ROS accumulation shorten the lifespan and those that reduce intracellular ROS extend lifespan.

Deletion of SODs Barker et al. On the other hand, overexpression of catalases Dai et al. Some mutants with extended lifespan are also found to be resistant to oxidative stress Lin et al. However, examples to the contrary also. Chapter 3, this volume; Mesquita et al.

An increase in intracellular oxidative stress and in ROS is detected in both chronologically and replicatively aged cells in the absence of any external stressors Fabrizio et al. The limitation of using yeast cells to study replicative ageing is the difficulty in obtaining truly old cells. However, several approaches have been employed to enrich for old cells. The most accurate method is micromanipulation of daughter cells away from mother cells and counting the number of generations produced by individual mother cells Mortimer and Johnston However, this method is not suitable for high throughput screening or most analytical techniques.

Sucrose density gradient can also be applied to separate young and old yeast cells Egilmez et al. Some use magnetic bead technology to immobilize yeast cells, wash away the daughter cells and re-culture the immobilized cells in fresh media and this process is repeated a few times Smeal et al. Although this approach give cells with similar age, it is not possible to isolate significant numbers of senescent cells.

The more recent elutriation centrifugation technique fractionates the cells based on size and is described in detail by Laun et al. For high throughput screening, an engineered strain, which only allows mother cells to divide when cells are grown on glucose can be used Jarolim et al. In this strain, the essential gene CDC6 is under the control of mother cell specific HO-promoter and the final optical density of the culture is directly proportional to the number of the cell divisions the strain has undergone.

The daughter cells arrest growth at the G1 phase of the cell cycle. The intriguing process that occurs during yeast budding is that the mother cells retain damaged proteins caused by oxidative stress asymmetric segregation and the biological clock of the daughter cell is set to zero Aguilaniu et al. The levels of carbonylated proteins and other forms of oxidatively damaged proteins are higher in mother cells than in the daughter cells Aguilaniu et al. The proteins targeted for oxidation during aging were found to be similar in both chronological and replicative ageing Reverter-Branchat et al.

Both stress-resistance proteins Hsp60p and Hsp70p and the enzymes involved in glucose metabolism appeared to be carbonylated in aged cells and those grown in high glucose concentration. This supports the view that damage caused by oxidative stress could be one cause of ageing. A functional actin cytoskeleton is important for the unequal distribution of the oxidized proteins and aggregates Aguilaniu et al. In addition to the restricted distribution of the damaged proteins, the daughter cells are also equipped with enhanced catalase activity to combat damage Erjavec and Nystrom Transcriptional analysis of the old cells versus young cells also shows that metabolism shifts from glycolysis to gluconeogenesis in aged cells Lesur and Campbell ; Lin et al.

Despite several observations that protein carbonyls and. It is interesting to note that chronologically old cells have accumulated death factors which can limit the replicative potential of those cells Ashrafi et al. This is one indication that replicative and chronological aging of yeast cells share some similarity despite the fact that the genome-wide analysis of both processes using the yeast deletion collection has revealed little overlap Laun et al.

However, this interesting observation depends on the carbon source and is not seen when yeast are grown on glycerol or ethanol Piper et al. As mentioned earlier, mitochondria are the major source of ROS. It was also suggested that inefficient respiration or defective mitochondrial activity found in aged Ermini ; Terman et al. However, high levels of ROS and carbonylated proteins are detected in yeast cells that are less than 10 generations old Aguilaniu et al. Treatments with different uncouplers of oxidative phosphorylation produce contradictory results: CCCP carbonyl cyanide 3-chlorophanylhydrazone causes an increase in ROS and shortens the replicative lifespan Stockl et al.

We have also found that ROS appeared after mitochondrial damage, which is probably triggered by a high level of glucose metabolites during chronological ageing. Therefore the role of mitochondria in aging is still not completely clear Breitenbach et al. Chapter 3, this volume. The assumption that eliminating the respiratory chain would also prevent oxygen toxicity also turns out to be wrong. A study of a respiratory-deficient mutant showed that there are cytoplasmic oxygen-dependent reactions that could give rise to oxygen toxicity Rosenfeld and Beauvoit ; Rosenfeld et al.

The chronological lifespan of the mutant is shorter than that of the wild-type cells Fabrizio et al. However, the replicative lifespan of mutants may be shorter Berger and Yaffe ; Powell et al. Analysis of the deletion mutants that affect both replicative and chronological ageing has highlighted the importance of respiratory functions for both forms of aging Laun et al. It was also shown that stationary phase cells pre-adapted to respiratory carbon source maintain their replicative capacity on glucose media compared to non-adapted cells Piper et al. One of the first genes identified by screening stress-resistant mutants for enhanced longevity was SIR4, which encodes a member of the Sir complex that mediates transcriptional repression at telomeres and the silent mating-type loci HML and HMR Kennedy et al.

Later another member of the Sir complex SIR2 was found to play a prominent role in ageing Guarente The second gene linked to yeast ageing in the initial screen was UTH1 Kennedy et al. Deletion of UTH1 increases replicative lifespan Kennedy et al. The link between longevity and the multifunctional Uth1p was intriguing at that time. Its importance for longevity may be based mechanistically on its role in apoptosis, autophagy, mitochondrial morphology, oxidative stress resistance or a combination of these processes.

The importance of autophagy and maintenance of mitochondrial morphology in ageing processes are increasingly evident Bergamini et al. Exactly how these conditions lengthen either lifespan is still not clear. The common responses that are up-regulated in both conditions are starvation response and autophagy. Autophagy recycles damaged organelles and provides nutrients for the cells when they are in need Cuervo ; Klionsky ; Klionsky and Emr ; Suzuki and Ohsumi It seems that cells grown under the conditions that favor low metabolic rates survive longer than those with high metabolic rates.

Functional stress resistance genes are still important for lifespan extension under these conditions. For example, the lifespan extension of ras2, cyr1 and sch9 mutants requires the SOD2 gene Fabrizio et al. There are some controversial results that lead to conclusion that lifespan can be extended without reduction of ROS. Certain yeast mutants live longer although they have increased intracellular ROS Kharade et al. Previously it was shown that providing antioxidants in the diet is beneficial for cell survival and cognitive performance in rodents Floyd In addition, the biological antioxidant glutathione is also found to be necessary to ensure the benefits of caloric restriction during ageing in yeast Mannarino et al.

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Evolution of Asymmetric Damage Segregation: A Modelling Approach

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Andrew Murray (Harvard) Part 1: Yeast Sex: An Introduction

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