Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

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.

Epigenetic regulation of aging stem cells

“…HATs are diverse in their structures and substrates and are often multisubunit complexes (Lee and Workman, 2007). HDACs can be divided into several classes based on sequence homology and cofactor dependency: class I, II and IV HDACs are classical HDACs requiring Zn 2 þ as a cofactor, whereas class III HDACs, also known as Sirtuins, require NAD þ as a cofactor (Imai et al, 2000;Haigis and Guarente, 2006;Yang and Seto, 2007). Control of histone acetylation is associated with longevity regulation in lower organisms (Kaeberlein et al, 1999;Tissenbaum and Guarente, 2001;Rogina and Helfand, 2004;Wood et al, 2004;Dang et al, 2009), and changes in histone acetylation in tissues, such as the brain and liver, correlate with age-dependent declines in tissue function (Oh and Conard, 1972;Shen et al, 2008;Kawakami et al, 2009;Peleg et al, 2010).…”

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…SIRT1 is a nicotinamide adenine dinucleotide (NAD+)‐dependent deacetylase that catalyzes the removal of acetyl groups from lysine residues on histone proteins, resulting in gene silencing (Braunstein, Rose, Holmes, Allis, & Broach, 1993; Imai, Armstrong, Kaeberlein, & Guarente, 2000; Tanny, Dowd, Huang, Hilz, & Moazed, 1999). SIRT1 also deacetylates transcription factors including PGC1α, which induces mitochondrial oxidative phosphorylation (Lagouge et al, 2006), p53, which promotes cell survival (Luo et al, 2001; Vaziri et al, 2001) and triggers adaptation to calorie restriction with its accompanying stress resistance (Guarente, 2013).…”

PLGA‐PNIPAM Microspheres Loaded with the Gastrointestinal Nutrient NaB Ameliorate Cardiac Dysfunction by Activating Sirt3 in Acute Myocardial Infarction

“…In case of the hydrolyzing of NAD + and transferring of the lysine‐bound acetyl group, the loop was moved, and the binding site was blocked, followed by activator release and deacetylated product dissociation. On the other hand, the hydrolyzed product of NAD + was nicotinamide (NAM), and the transferred product of the lysine‐bound acetyl group was 2′‐O‐acetyl adenosine diphosphate(ADP)‐ribose; NAM was transferred to nicotinamide mononucleotide(NMN) by nicotinamide phosphoribosyl transferase (NAMPT), and then the NMN was transferred back to NAD + by nicotinamide mononucleotide adenylyltransferase (NMNAT), forming the NAD + cycle 22, 23. The above results indicated that NaB could contribute to the stabilization of the Sirt3/substrate complex by ordering the “adaptable loop”, leading to the deacetylation of the enzyme for the substrate through stabilized exposure to the “active site”.…”