Journal ArticleDOI
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
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TLDR
The analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo, and provides a molecular framework of NAD-dependent histone de acetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.Abstract:
Yeast Sir2 is a heterochromatin component that silences transcription at silent mating loci, telomeres and the ribosomal DNA, and that also suppresses recombination in the rDNA and extends replicative life span. Mutational studies indicate that lysine 16 in the amino-terminal tail of histone H4 and lysines 9, 14 and 18 in H3 are critically important in silencing, whereas lysines 5, 8 and 12 of H4 have more redundant functions. Lysines 9 and 14 of histone H3 and lysines 5, 8 and 16 of H4 are acetylated in active chromatin and hypoacetylated in silenced chromatin, and overexpression of Sir2 promotes global deacetylation of histones, indicating that Sir2 may be a histone deacetylase. Deacetylation of lysine 16 of H4 is necessary for binding the silencing protein, Sir3. Here we show that yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, which deacetylate lysines 9 and 14 of H3 and specifically lysine 16 of H4. Our analysis of two SIR2 mutations supports the idea that this deacetylase activity accounts for silencing, recombination suppression and extension of life span in vivo. These findings provide a molecular framework of NAD-dependent histone deacetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes.read more
Citations
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Translating the Histone Code
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TL;DR: It is proposed that this epigenetic marking system represents a fundamental regulatory mechanism that has an impact on most, if not all, chromatin-templated processes, with far-reaching consequences for cell fate decisions and both normal and pathological development.
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Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
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TL;DR: The potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating Sirt1-dependent deacetylation of p53.
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Retrospective study: The diagnostic accuracy of conventional forceps biopsy of gastric epithelial compared to endoscopic submucosal dissection (STROBE compliant).
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Journal ArticleDOI
Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase
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References
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Journal ArticleDOI
The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms
TL;DR: It is shown that life span regulation by the Sir proteins is independent of their role in nonhomologous end joining, and increasing the gene dosage extends the life span in wild-type cells.
Journal ArticleDOI
Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A.
TL;DR: Results clearly indicate that TSA is a potent and specific inhibitor of the histone deacetylase and that the in vivo effect of TSA on cell proliferation and differentiation can be attributed to the inhibition of the enzyme.
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A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p.
TL;DR: A role for histone deacetylase as a key regulator of eukaryotic transcription is supported by the predicted protein, which is very similar to the yeast transcriptional regulator Rpd3p.
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Extrachromosomal rDNA circles--a cause of aging in yeast.
TL;DR: It is shown that nucleolar changes in aging yeast mother cells are likely due to the accumulation of extrachromosomal rDNA circles (ERCs) in old cells and that, in fact, ERCs cause aging.
Journal ArticleDOI
Position Effect at S. cerevisiae Telomeres: Reversible Repression of Pol II Transcription
TL;DR: Yeast telomeres exert a position effect on the transcription of nearby genes, an effect that is under epigenetic control as demonstrated by phenotype and mRNA analyses.