Imai S, Armstrong C M, Kaeberlein M, Guarente L
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA.
Nature. 2000 Feb 17;403(6771):795-800. doi: 10.1038/35001622.
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.
酵母Sir2是一种异染色质成分，它能使沉默的交配位点、端粒和核糖体DNA处的转录沉默，还能抑制核糖体DNA中的重组并延长复制寿命。突变研究表明，组蛋白H4氨基末端尾巴上的赖氨酸16以及H3中的赖氨酸9、14和18在沉默过程中至关重要，而H4的赖氨酸5、8和12具有更多冗余功能。组蛋白H3的赖氨酸9和14以及H4的赖氨酸5、8和16在活性染色质中被乙酰化，在沉默染色质中低乙酰化，并且Sir2的过表达促进组蛋白的整体去乙酰化，这表明Sir2可能是一种组蛋白脱乙酰酶。H4赖氨酸16的去乙酰化是结合沉默蛋白Sir3所必需的。我们在此表明，酵母和小鼠Sir2蛋白是烟酰胺腺嘌呤二核苷酸（NAD）依赖性组蛋白脱乙酰酶，它们使H3的赖氨酸9和14以及特异性地使H4的赖氨酸16去乙酰化。我们对两个SIR2突变的分析支持了这样一种观点，即这种脱乙酰酶活性解释了体内的沉默、重组抑制和寿命延长。这些发现提供了一个NAD依赖性组蛋白去乙酰化的分子框架，它将酵母以及可能在高等真核生物中的代谢、基因组沉默和衰老联系起来。
