Transcriptional Silencing and Longevity Protein Sir2
Author and Curator: Larry H Bernstein, MD, FCAP Author and Curator:
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase.
Imai S1, Armstrong CM, Kaeberlein M, Guarente L.
Nature. Feb 17, 2000; 403(6771): 795-800. PMID: 10693811
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.
2012pharmaceutical
sjwilliamspa