Aerobic and anaerobic NAD<sup>+</sup> metabolism in <i>Saccharomyces cerevisiae</i>

Panozzo, Cristina; Nawara, Magdalena; Suski, Catherine; Kucharczyk, Róża; Skoneczny, Marek; Bécam, Anne Marie; Rytka, Joanna; Herbert, Christopher J.

doi:10.1016/s0014-5793(02)02585-1

Cited by 154 publications

(155 citation statements)

References 17 publications

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“…Second, we observed induction of a homologue of indoleamine-2,3-dioxygenase (H.c. IDO1), an enzyme in the kynurenine pathway. This protein modifies tryptophan during the first step in NAD ϩ synthesis (Panozzo et al, 2002). NAD ϩ is required for energy production and DNA repair, among other cellular processes.…”

Section: Homologues Of Known Rns-response or Stress-response Genesmentioning

confidence: 99%

Identification ofHistoplasma capsulatumTranscripts Induced in Response to Reactive Nitrogen Species

Nittler

Hocking-Murray

Foo

et al. 2005

MBoC

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The pathogenic fungus Histoplasma capsulatum escapes innate immune defenses and colonizes host macrophages during infection. After the onset of adaptive immunity, the production of the antimicrobial effector nitric oxide ( ⅐ NO) restricts H. capsulatum replication. However, H. capsulatum can establish persistent infections, indicating that it survives in the host despite exposure to reactive nitrogen species (RNS). To understand how H. capsulatum responds to RNS, we determined the transcriptional profile of H. capsulatum to ⅐ NO-generating compounds using a shotgun genomic microarray. We identified 695 microarray clones that were induced >4-fold upon nitrosative stress. Because our microarray clones were generated from random fragments of genomic DNA, they did not necessarily correspond to H. capsulatum open reading frames. To identify induced genes, we used high-density oligonucleotide tiling arrays to determine the genomic boundaries and coding strand of 153 RNS-induced transcripts. Homologues of these genes in other organisms are involved in iron acquisition, energy production, stress response, protein folding/degradation, DNA repair, and ⅐ NO detoxification. Ectopic expression of one of these genes, a P450 nitric oxide reductase homologue, was sufficient to increase resistance of H. capsulatum to RNS in culture. We propose that H. capsulatum uses the pathways identified here to cope with RNS-induced damage during pathogenesis.

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Section: Homologues Of Known Rns-response or Stress-response Genesmentioning

confidence: 99%

Identification ofHistoplasma capsulatumTranscripts Induced in Response to Reactive Nitrogen Species

Nittler

Hocking-Murray

Foo

et al. 2005

MBoC

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“…1), the Hst1p sirtuin is responsible for activation of BNA2, which encodes the enzyme that catalyzes the first step in the pathway for the de novo synthesis of NAD ϩ from tryptophan ( Fig. 1) (34,35). However, BNA2 was also found to be up-regulated in microarray studies of cells grown in the absence of inositol (1,2) and in cells grown at 37°C (36), a stress condition that, similar to inositol starvation, activates PKC signaling (37).…”

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confidence: 99%

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Lee¹,

Gaspar²,

Aregullin

et al. 2013

Journal of Biological Chemistry

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Background: Inhibition of complex sphingolipid synthesis by inositol starvation activates the PKC-MAPK signaling pathway. Results: Sir2p-dependent telomeric silencing is activated by interrupting sphingolipid synthesis and requires the MAPK, Slt2p. Conclusion: Telomeric silencing is regulated by PKC-MAPK signaling in response to interruption of sphingolipid synthesis. Significance: Sphingolipid metabolism plays an important role in regulating silencing and chronological life span.

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“…The sensitivity of urh1D mutants to DNA damage may be attributable to its role in salvaging pyrimidine deoxyribonucleosides (Kurtz et al 2002;Mitterbauer et al 2002), high levels of which may facilitate DNA repair (Sirbu and Cortez 2013). Nicotinamide had no effect on the MMS sensitivity of a bna2D mutant, which is defective in de novo synthesis of NAD+ from tryptophan ( Figure 4A) (Panozzo et al 2002). Notably, nicotinamide enhanced the MMS resistance of msn2D msn4D strains ( Figure 4B), wherein Pnc1 levels remained at basal levels after MMS treatment ( Figure 3D).…”

Section: Mms Sensitivity Of Nad+ Biosynthetic Mutantsmentioning

confidence: 99%

“…It is normally cleared by the nicotinamide salvage pathway, which also contributes to the maintenance of NAD+ levels within the cell (Gallo et al 2004;Sauve et al 2005;McClure et al 2008). NAD+ can also be produced de novo from tryptophan in a pathway requiring Bna2 (Panozzo et al 2002). Exogenously added nicotinamide is used to inhibit sirtuins at concentrations of 5-25 mM (Bitterman et al 2002;Tsuchiya et al 2006).…”

mentioning

confidence: 99%

Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases

et al. 2016

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Nicotinamide is both a reaction product and an inhibitor of the conserved sirtuin family of deacetylases, which have been implicated in a broad range of cellular functions in eukaryotes from yeast to humans. Phenotypes observed following treatment with nicotinamide are most often assumed to stem from inhibition of one or more of these enzymes. Here, we used this small molecule to inhibit multiple sirtuins at once during treatment with DNA damaging agents in the Saccharomyces cerevisiae model system. Since sirtuins have been previously implicated in the DNA damage response, we were surprised to observe that nicotinamide actually increased the survival of yeast cells exposed to the DNA damage agent MMS. Remarkably, we found that enhanced resistance to MMS in the presence of nicotinamide was independent of all five yeast sirtuins. Enhanced resistance was also independent of the nicotinamide salvage pathway, which uses nicotinamide as a substrate to generate NAD+, and of a DNA damage-induced increase in the salvage enzyme Pnc1. Our data suggest a novel and unexpected function for nicotinamide that has broad implications for its use in the study of sirtuin biology across model systems.KEYWORDS nicotinamide; sirtuins; DNA damage; checkpoint; Pnc1; NAD+ T HE DNA damage checkpoint is a highly conserved signaling cascade initiated in response to DNA lesions. In the budding yeast Saccharomyces cerevisiae, checkpoint activation begins with the exposure of single-stranded DNA (ssDNA), either from exonuclease-resected DNA doublestrand breaks (DSBs), or from stalled replication forks during S phase. Resected DNA coated by the ssDNA binding protein RPA is thought to act as a landing pad for Mec1-Ddc2 complexes (Melo and Toczyski 2002;Gobbini et al. 2013;Edenberg et al. 2014a). Mec1 is a sensor kinase that, in concert with adaptor proteins such as Rad9 or Mrc1, phosphorylates downstream checkpoint targets, including the Rad53 and Chk1 transducing kinases (Melo and Toczyski 2002;Gobbini et al. 2013; Bastos de Oliveira et al. 2015). Following autophosphorylation and release from adaptors, Rad53 is thought to move throughout the cell to phosphorylate targets that promote cell cycle arrest, the inhibition of late-firing origins of replication, and a global transcriptional response (Melo and Toczyski 2002;Jaehnig et al. 2013;Edenberg et al. 2014a). While the DNA damage response is traditionally associated with phosphorylationbased signaling cascades, it has recently emerged that other post-translational modifications including ubiquitylation, sumoylation, and acetylation play prominent roles in the response in both yeast and other eukaryotes (Downey and Durocher 2006a;Psakhye and Jentsch 2012;Panier and Durocher 2013;Edenberg et al. 2014a;Elia et al. 2015).Acetylation of lysine residues is catalyzed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs). Despite their names, these enzymes also have nonhistone targets that play critical roles in maintaining cellular homeostasis in organisms from ba...

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Aerobic and anaerobic NAD⁺ metabolism in Saccharomyces cerevisiae

Cited by 154 publications

References 17 publications

Identification ofHistoplasma capsulatumTranscripts Induced in Response to Reactive Nitrogen Species

Identification ofHistoplasma capsulatumTranscripts Induced in Response to Reactive Nitrogen Species

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases

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Aerobic and anaerobic NAD+ metabolism in Saccharomyces cerevisiae

Cited by 154 publications

References 17 publications

Identification ofHistoplasma capsulatumTranscripts Induced in Response to Reactive Nitrogen Species

Identification ofHistoplasma capsulatumTranscripts Induced in Response to Reactive Nitrogen Species

Activation of Protein Kinase C-Mitogen-activated Protein Kinase Signaling in Response to Inositol Starvation Triggers Sir2p-dependent Telomeric Silencing in Yeast

Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases

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Aerobic and anaerobic NAD⁺ metabolism in Saccharomyces cerevisiae