scholarly journals Transcriptional Repression by Neuron-Restrictive Silencer Factor Is Mediated via the Sin3-Histone Deacetylase Complex

2000 ◽  
Vol 20 (6) ◽  
pp. 2147-2157 ◽  
Author(s):  
Avtar Roopra ◽  
Lisa Sharling ◽  
Ian C. Wood ◽  
Teresa Briggs ◽  
Ulla Bachfischer ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Gene Transcription ◽  
Transcriptional Repression ◽  
Neuronal Cell ◽  
Dominant Negative ◽  
Specific Gene ◽  
Aberrant Expression ◽  
Neuronal Gene ◽  
Repressor Element

ABSTRACT A large number of neuron-specific genes characterized to date are under the control of negative transcriptional regulation. Many promoter regions of neuron-specific genes possess the repressor element repressor element 1/neuron-restrictive silencing element (RE1/NRSE). Its cognate binding protein, REST/NRSF, is an essential transcription factor; its null mutations result in embryonic lethality, and its dominant negative mutants produce aberrant expression of neuron-specific genes. REST/NRSF acts as a regulator of neuron-specific gene expression in both nonneuronal tissue and developing neurons. Here, we shown that heterologous expression of REST/NRSF inSaccharomyces cerevisiae is able to repress transcription from yeast promoters engineered to contain RE1/NRSEs. Moreover, we have taken advantage of this observation to show that this repression requires both yeast Sin3p and Rpd3p and that REST/NRSF physically interacts with the product of the yeast SIN3 gene in vivo. Furthermore, we show that REST/NRSF binds mammalian SIN3A and HDAC-2 and requires histone deacetylase activity to repress neuronal gene transcription in both nonneuronal and neuronal cell lines. We show that REST/NRSF binding to RE1/NRSE is accompanied by a decrease in the acetylation of histones around RE1/NRSE and that this decrease requires the N-terminal Sin3p binding domain of REST/NRSF. Taken together, these data suggest that REST/NRSF represses neuronal gene transcription by recruiting the SIN3/HDAC complex.

scholarly journals DNA Binding-Independent Induction of IκBα Gene Transcription by PPARα

2002 ◽  
Vol 16 (5) ◽  
pp. 1029-1039 ◽  
Author(s):  
Philippe Delerive ◽  
Karolien De Bosscher ◽  
Wim Vanden Berghe ◽  
Jean-Charles Fruchart ◽  
Guy Haegeman ◽  
...  
Keyword(s):  
Gene Transcription ◽  
Transcriptional Repression ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Dominant Negative ◽  
Site Directed Mutagenesis ◽  
Dependent Manner ◽  
Response Element

Abstract PPARs are ligand-activated transcription factors that regulate energy homeostasis. In addition, PPARs furthermore control the inflammatory response by antagonizing the nuclear factor-κB (NF-κB) signaling pathway. We recently demonstrated that PPARα activators increase IκBα mRNA and protein levels in human aortic smooth muscle cells. Here, we studied the molecular mechanisms by which PPARα controls IκBα expression. Using transient transfection assays, it is demonstrated that PPARα potentiates p65-stimulated IκBα transcription in a ligand-dependent manner. Site-directed mutagenesis experiments revealed that PPARα activation of IκBα transcription requires the NF-κB and Sp1 sites within IκBα promoter. Chromatin immunoprecipitation assays demonstrate that PPARα activation enhances the occupancy of the NF-κB response element in IκBα promoter in vivo. Overexpression of the oncoprotein E1A failed to inhibit PPARα-mediated IκBα promoter induction, suggesting that cAMP response element binding protein-binding protein/p300 is not involved in this mechanism. By contrast, a dominant-negative form of VDR-interacting protein 205 (DRIP205) comprising its two LXXLL motifs completely abolished PPARα ligand-mediated activation. Furthermore, cotransfection of increasing amounts of DRIP205 relieved this inhibition, suggesting that PPARα requires DRIP205 to regulate IκBα promoter activity. By contrast, DRIP205 is not involved in PPARα-mediated NF-κB transcriptional repression. Taken together, these data provide a molecular basis for PPARα-mediated induction of IκBα and demonstrate, for the first time, that PPARα may positively regulate gene transcription in the absence of functional PPAR response elements.

scholarly journals CHOP Enhancement of Gene Transcription by Interactions with Jun/Fos AP-1 Complex Proteins

1999 ◽  
Vol 19 (11) ◽  
pp. 7589-7599 ◽  
Author(s):  
Mariano Ubeda ◽  
Mario Vallejo ◽  
Joel F. Habener
Keyword(s):  
Transcription Factor ◽  
Gene Transcription ◽  
Stress Responses ◽  
Leucine Zipper ◽  
Target Genes ◽  
Cellular Stress ◽  
Dominant Negative ◽  
Dimerization Domain ◽  
Mobility Shift

ABSTRACT The transcription factor CHOP (C/EBP homologous protein 10) is a bZIP protein induced by a variety of stimuli that evoke cellular stress responses and has been shown to arrest cell growth and to promote programmed cell death. CHOP cannot form homodimers but forms stable heterodimers with the C/EBP family of activating transcription factors. Although initially characterized as a dominant negative inhibitor of C/EBPs in the activation of gene transcription, CHOP-C/EBP can activate certain target genes. Here we show that CHOP interacts with members of the immediate-early response, growth-promoting AP-1 transcription factor family, JunD, c-Jun, and c-Fos, to activate promoter elements in the somatostatin, JunD, and collagenase genes. The leucine zipper dimerization domain is required for interactions with AP-1 proteins and transactivation of transcription. Analyses by electrophoretic mobility shift assays and by an in vivo mammalian two-hybrid system for protein-protein interactions indicate that CHOP interacts with AP-1 proteins inside cells and suggest that it is recruited to the AP-1 complex by a tethering mechanism rather than by direct binding of DNA. Thus, CHOP not only is a negative or a positive regulator of C/EBP target genes but also, when tethered to AP-1 factors, can activate AP-1 target genes. These findings establish the existence of a new mechanism by which CHOP regulates gene expression when cells are exposed to cellular stress.

A repressor controls the timing and spatial localisation of stalk cell-specific gene expression in Dictyostelium

Development ◽  
1993 ◽  
Vol 118 (4) ◽  
pp. 1041-1048 ◽  
Author(s):  
A.J. Harwood ◽  
A. Early ◽  
J.G. Williams
Keyword(s):  
Gene Expression ◽  
Transcriptional Repression ◽  
Consensus Sequence ◽  
Matrix Proteins ◽  
Stalk Cell ◽  
Specific Gene ◽  
Gene Mutant ◽  
Dependent Protein ◽  
Apical Papilla ◽  
Repressor Element

The ecmA and ecmB genes of Dictyostelium encode related extracellular matrix proteins and both are induced by DIF, the stalk cell-specific morphogen. The ecmA gene is expressed throughout the prestalk region of the migrating slug but only later, at culmination, do the prestalk cells express the ecmB gene. Expression of the ecmB gene is induced at the entrance to the stalk tube and we have identified two, apparently redundant, promoter elements that control this process. They act as repressors, preventing transcription in the tip of the migrating slug and the apical papilla of the culminant. They have a semi-palindromic consensus sequence TTGnCAA, where n is in one case 2 and in the other 4 bp. Either element alone is able to repress ecmB promoter activity in prestalk cells. Introduction of a single repressor element into the promoter of the ecmA gene changes its expression pattern to resemble that of the ecmB gene. Mutant elements, where n is altered, cause repression during the slug stage but allow premature ecmB expression during culmination; suggesting that the effective strength of the inductive signal may increase during culmination. Inhibition of cAMP-dependent protein kinase (PKA) in prestalk cells blocks both stalk cell maturation and ecmB gene expression. We show that the block to gene expression correlates precisely with the presence of a functional repressor element and this is consistent with the notion that expression of the ecmB gene is controlled by a PKA-dependent release from transcriptional repression.

Evi-1 Interacts with Histone Methyltransferases for Transcription Repression and Bone Marrow Transformation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2257-2257
Author(s):  
Susumu Goyama ◽  
Eriko Nitta ◽  
Munetake Shimabe ◽  
Tetsuya Yoshino ◽  
Shinichi Kako ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histone Modifications ◽  
Transcriptional Repression ◽  
Integration Site ◽  
Dominant Negative ◽  
Luciferase Reporter ◽  
Deletion Mutants ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Transcription Repression

Abstract Evi-1 (ecotropic viral integration site-1) is a nuclear transcription factor containing multiple zinc finger motifs, and plays an essential role in the proliferation/maintenance of hematopoietic stem cells. Aberrant expression of Evi-1 has been frequently found in myeloid leukemia as well as in several solid tumors, and is associated with a poor patient survival. It has been shown that Evi-1 acts as a transcriptional repressor through its interaction with several transcriptional regulators, including C-terminal binding protein (CtBP), histone deacetylases (HDACs), and Smad3. Numerous studies have shown that cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. Methylation of histone H3 lysine 9 (H3K9) is one of the most well-studied histone modifications. After the initial identification of SUV39H1 as a H3K9-specific histone methyltransferase (HMT), at least three other HMTs, G9a, GLP, and SETDB1, have been recognized as HMTs for H3K9 in mammals. Very recently, several groups reported that Evi-1 physically interacts with H3K9 HMTs, SUV39H1 and G9a. However, the functional roles of the HMTs in Evi-1-mediated leukemogenesis remain unclear. In this study, we first showed that Evi-1 physically interacts with SUV39H1 and G9a in 293T cells using immunoprecipitation experiments. Immunofluorescence analysis also revealed that Evi-1 co-localizes with these HMTs in COS7 cells. Thus, Evi-1 forms a complex with these HMTs in vivo. We then attempted to map the region of Evi-1 that is necessary for interaction with the HMTs using Evi-1 deletion mutants which lack various functional domains. In contrast to the previous reports, all of these deletion mutants associate with both SUV39H1 and G9a almost as efficiently as full-length Evi-1, suggesting that interaction between Evi-1 and the HMTs is mediated through a relatively wide stretch of multiple regions. We further showed that both Evi-1-SUV39H1 and Evi-1-G9a complexes are able to methylate recombinant H3 using in vitro histone methylation assay, suggesting that the proteins form an active complex with methyltransferase activity. Next, we performed a luciferase reporter assay to determine whether the HMTs are actively involved in Evi-1-mediated transcriptional repression of the p3TP promoter, which is induced strongly by TGF-β. As we have shown previously, co-transfection of Evi-1 together with p3TP-Lux resulted in repression of reporter activity. Interestingly, catalytically inactive forms of SUV39H1 and G9a, carrying a point mutation within the HMT domain, were able to abrogate the transcriptional repression mediated by Evi-1. Because the inactive mutants were still able to associate with Evi-1 in immunoprecipitation studies, they might act as dominant-negative mutants, competing with endogenous HMTs. Finally, we evaluated a role for the HMTs in Evi-1-induced myeloid transformation. Bone marrow progenitors transduced with Evi-1 showed sustained colony formation in the serial replating assay. After establishment of sustained clonogenic activity following more than three rounds of replating in methylcellulose medium, the cells were transduced with SUV39H1-shRNA, G9a-shRNA or control-shRNA. Remarkably, RNAi-based knockdown of these HMTs in Evi-1-transformed progenitors markedly reduced their colony-forming activity. Taken together, these results indicate that Evi-1 can act as a transcriptional regulator that is able to form higher order complexes with HMTs, and this association has a role in the transcription repression and leukemia development. Therefore, epigenetic modifications mediated by SUV39H1 and G9a could be valid therapeutic targets in Evi-1-related hematological malignancies.

scholarly journals MafG Sumoylation Is Required for Active Transcriptional Repression

2006 ◽  
Vol 26 (12) ◽  
pp. 4652-4663 ◽  
Author(s):  
Hozumi Motohashi ◽  
Fumiki Katsuoka ◽  
Chika Miyoshi ◽  
Yasuhiro Uchimura ◽  
Hisato Saitoh ◽  
...  
Keyword(s):  
Binding Site ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Cultured Cells ◽  
Physiological Role ◽  
Histone Deacetylase Inhibition ◽  
Dna Binding Site ◽  
Repressor Complex ◽  
Repressor Activity

ABSTRACT A straightforward mechanism for eliciting transcriptional repression would be to simply block the DNA binding site for activators. Such passive repression is often mediated by transcription factors that lack an intrinsic repressor activity. MafG is a bidirectional regulator of transcription, a repressor in its homodimeric state but an activator when heterodimerized with p45. Here, we report that MafG is conjugated to SUMO-2/3 in vivo. To clarify the possible physiological role(s) for sumoylation in regulating MafG activity, we evaluated mutant and wild-type MafG in transgenic mice and cultured cells. Whereas sumoylation-deficient MafG activated p45-dependent transcription normally and did not affect heterodimer activity, repression by the sumoylation-deficient MafG mutant was severely compromised in vivo. Furthermore, the SUMO-dependent repression activity of MafG was sensitive to histone deacetylase inhibition. Thus, repression by MafG is not achieved through simple passive repression by competing for the activator binding site but requires sumoylation, which then mediates transcriptional repression through recruitment of a repressor complex containing histone deacetylase activity.

scholarly journals Architectural Transcription Factor HMGI(Y) Promotes Tumor Progression and Mesenchymal Transition of Human Epithelial Cells

2001 ◽  
Vol 21 (2) ◽  
pp. 575-594 ◽  
Author(s):  
Raymond Reeves ◽  
Dale D. Edberg ◽  
Ying Li
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Nude Mice ◽  
Epithelial Mesenchymal Transition ◽  
Neoplastic Transformation ◽  
Dominant Negative ◽  
Metastatic Progression ◽  
Aberrant Expression ◽  
Mesenchymal Transition

ABSTRACT Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events.

In vivo regulation of growth hormone-stimulated gene transcription by STAT5b

2004 ◽  
Vol 286 (3) ◽  
pp. E393-E401 ◽  
Author(s):  
Joachim Woelfle ◽  
Peter Rotwein
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Growth Hormone ◽  
Gene Transfer ◽  
Gene Transcription ◽  
Dominant Negative ◽  
Signal Transduction Pathways ◽  
Igf I ◽  
Igfbp 3

The long-term effects of growth hormone (GH) are mediated through coordinated changes in gene expression that are the outcome of interactions between hormone-activated signal transduction pathways and specific feedback loops. Recent studies in mice have implicated the transcription factor STAT5b as part of the GH-regulated somatic growth pathway, because mice lacking this protein showed diminished growth rates. To assess the role of Stat5b in GH-stimulated gene expression, we have delivered modified versions of the protein to the liver of pituitary-deficient male rats by quantitative adenovirus-mediated gene transfer. In pilot studies in cell culture, both constitutive-active and dominant-negative STAT5b showed appropriate binding properties toward a specific DNA response element. After in vivo expression, neither protein prevented nuclear accumulation of STATs 1 and 3 in the liver. Dominant-negative STAT5b completely inhibited GH-stimulated transcription of genes encoding the growth-promoting proteins IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS), which comprise the major circulating IGF-I complex, and blocked expression of the GH inhibitors SOCS-1, SOCS-2, and CIS, but had little effect on induction of SOCS-3. Constitutive-active STAT5b stimulated robust transcription of IGF-I, ALS, and IGFBP-3 in the absence of hormone but did little to modify GH-mediated activation of SOCS family genes. An adenovirus encoding EGFP was without effect. These results, in addition to establishing STAT5b as one of the key agents of GH-stimulated gene transcription, demonstrate the feasibility of using in vivo gene transfer to target and dissect the functions of distinct components of complex hormone-activated signal transduction pathways.

Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 359-359
Author(s):  
Fabien Guidez ◽  
Louise Howell ◽  
Mark Isalan ◽  
Marek Cebrat ◽  
Rhoda M. Alani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Binding ◽  
Histone Deacetylase ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Hematopoietic Stem

Abstract The Promyelocytic Leukemia Zinc Finger (PLZF) gene was identified in a rare case of acute promyelocytic leukemia (APL) with translocation t(11;17)(q23;q21) and resistance to therapy with all-trans-retinoic acid. Recent studies have indicated a critical role of PLZF in maintenance of spermatogonial stem cells. Prominent expression of PLZF in hematopoietic stem cells, suggest that it may also play a similar role in this compartment. The wild type PLZF protein is a DNA sequence-specific transcription repressor containing nine Krüppel-like C2-H2 zinc fingers and an N-terminal BTB/POZ repression domain. Transcriptional repression by PLZF is mediated through recruitment of the nuclear receptor co-repressor (N-CoR/SMRT)/histone deacetylase (HDAC) complexes to its target genes, such as c-MYC and HOX genes. We now show that transcriptional repression by PLZF is surprisingly also dependent on the histone acetyl transferase (HAT) activity of the p300 protein. PLZF associates with p300 in vivo and its ability to repress transcription is specifically dependent on acetylation of PLZF on lysines in its C-terminal C2-H2 zinc-finger motifs. Acetylation of PLZF enhances its ability to bind its cognate DNA binding site in vitro as determined by EMSA and in vivo as measured by chromatin immunoprecipitation. An acetylation site mutant of PLZF fails to repress transcription despite retaining its abilities to interact with co-repressor/HDAC complexes, due to inefficient DNA binding. Inhibitors of p300 abolish transcriptional repression by PLZF and mutants of PLZF that mimic acetylation were insensitive to these inhibitory effects. Acetylation of PLZF by p300 was specific since over-expression of another HAT, p/CAF or the selective inhibition of p/CAF had no effect on PLZF activity despite the ability of the proteins to associate with each other. Taken together, our results indicate that a histone deacetylase dependent transcriptional repressor can be positively regulated through acetylation and point to an unexpected role of a co-activator protein in transcriptional repression.

Identification of Key Cellular Regulators That Interact with Id1 To Control Hematopoietic Stem Cell Behavior.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1319-1319
Author(s):  
Vladimir Jankovic ◽  
Alessia Ciarrocchi ◽  
Tony DeBlasio ◽  
Robert Benezra ◽  
Stephen D. Nimer
Keyword(s):  
Transcription Factors ◽  
Transcriptional Repression ◽  
Genetic Interaction ◽  
Dominant Negative ◽  
Double Knockout ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Helix Loop Helix

Abstract The ability of hematopoietic stem cells to tightly regulate the transition from relative quiescence and self-renewal to the transiently amplifying, differentiating progenitor fate is critical for HSC homeostasis as well as their regenerative capacity. We have recently described the diminished frequency and rapid exhaustion of HSC self-renewal capacity in the absence of the dominant negative helix-loop-helix molecule Id1. Furthermore, Id1 null HSCs have an increased rate of cycling, coupled with accelerated myeloid commitment both in vivo and in vitro. This is reflected in the elevated expression of myelo-erythroid transcription factors (c/EBPalpha and GATA1) within the Lin−c-kit+Sca-1+ population - “myeloid priming”. The major targets of Id1 mediated transcriptional repression are the ubiquitous E protein E2A as well as Ets transcription factors (Ets1 and Ets2). We hypothesized that the unrestrained activity of these and/or other targets of Id1 transcriptional repression leads to premature HSC commitment in Id1 null animals. Indeed, we show that HSC differentiation in culture can be delayed by transduction of E2A directed shRNA specifically in Id1 null, but not in wild-type Id1 expressing cells. This indicates an abnormal E2A activity in Id1 null HSCs that could be responsible for their increased differentiation status. To further define the transcriptional deregulation in Id1 null HSCs, we have used the Affymetrix microarray technology. We observed ~3 fold increased expression of the CDK inhibitor p21 in freshly isolated Id1 null HSCs and have confirmed this result by multiple independent qPCR measurements. The transcriptional induction of p21 by E2A as well as its repression by Id1 have been well established. Therefore, the observed p21 induction could be explained by the elevated level of E2A activity in HSCs in the absence of Id1 expression. To explore the functional significance of Id1 mediated p21 regulation in HSCs, we have generated p21/Id1 double knockout animals. Surprisingly, despite its reported function in restricting the cell cycle entry of normal HSCs, we show that in the context of Id1 loss, p21 expression is required for the accelerated HSC cycling, and unlike Id1 single null HSCs, p21/Id1 double knockout HSCs do not show accelerated myeloid differentiation in culture. Therefore, we propose that Id1 actively represses E2A activity in HSCs, as well as the induction of p21, which could be an important component of the HSC commitment program. Further studies will be presented defining the in vivo relevance of the Id1/p21 genetic interaction for HSC growth and differentiation.

scholarly journals Nicotinamide Clearance by Pnc1 Directly Regulates Sir2-Mediated Silencing and Longevity

2004 ◽  
Vol 24 (3) ◽  
pp. 1301-1312 ◽  
Author(s):  
Christopher M. Gallo ◽  
Daniel L. Smith ◽  
Jeffrey S. Smith
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nicotinic Acid ◽  
Life Span ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Transcriptional Silencing ◽  
Inhibitory Effect ◽  
Salvage Pathway

ABSTRACT The Saccharomyces cerevisiae Sir2 protein is an NAD+-dependent histone deacetylase (HDAC) that functions in transcriptional silencing and longevity. The NAD+ salvage pathway protein, Npt1, regulates Sir2-mediated processes by maintaining a sufficiently high intracellular NAD+ concentration. However, another NAD+ salvage pathway component, Pnc1, modulates silencing independently of the NAD+ concentration. Nicotinamide (NAM) is a by-product of the Sir2 deacetylase reaction and is a natural Sir2 inhibitor. Pnc1 is a nicotinamidase that converts NAM to nicotinic acid. Here we show that recombinant Pnc1 stimulates Sir2 HDAC activity in vitro by preventing the accumulation of NAM produced by Sir2. In vivo, telomeric, rDNA, and HM silencing are differentially sensitive to inhibition by NAM. Furthermore, PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, life span, and Hst1-mediated transcriptional repression. Finally, we show that stress suppresses the inhibitory effect of NAM through the induction of PNC1 expression. Pnc1, therefore, positively regulates Sir2-mediated silencing and longevity by preventing the accumulation of intracellular NAM during times of stress.

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