SIR proteins

[6] The authors reasoned that the mutation caused the de-repression of then-recently appreciated silent mating type loci HMa and HMα, which would allow an a/a diploid to sporulate and would cause haploid segregants inheriting the mutant allele to behave as a/α diploids despite being haploid.

Specifically, Rine & Herskowitz reasoned that a haploid yeast cell with a recessive mutation in matα1 could be complemented if the silent copy of MATα were de-repressed.

[11] Later it would be shown that in yeast and in higher organisms, SIR proteins are important for transcriptional regulation of many chromatin domains.

In budding yeast, SIR proteins are found at the silent mating type loci, telomeres, and at the rDNA locus.

At the silent mating type loci and at the telomeres, SIR proteins participate in transcriptional silencing of genes within their domain of localization.

In yeast, SIR proteins bind sites on nucleosome tails and form a multimeric compound of SIR2,3,4 that condenses chromatin and is thought to physically occlude promoters in the silenced interval, preventing their interaction with transcription machinery.

Sir2 then deacetylates histone H3 and H4 tails, and free Sir3 binds the now-deacetylated lysine residues H4K16,79, and recruits additional Sir4-Sir2 dimers to promote the further spreading of the heterochromatin domain.

[12] Once it has spread to cover a genomic locus, the SIR2,3,4 effectively prevents transcription from the region it occupies, in a process that is thought to depend on the physical occlusion of DNA by SIR proteins.

Recently, it has been shown that certain promoters are capable of directing transcription inside regions that are otherwise silenced by SIR proteins.

[12] It was the first-discovered member of the Sirtuin protein family and it is highly conserved, with homologs found in organisms ranging from humans to bacteria[16] and archaea.

[12] It interacts with a variety of protein substrates, but does not exhibit strong affinity for DNA, chromatin, or other silencer-binding factors.

[12] SIR proteins are conserved from yeast to humans, and lend their name to a class of mammalian histone deacetylases (Sirtuins, homologs of Sir2).

Sirtuins have been implicated in myriad human traits including Alzheimer's and diabetes, and have been proposed to regulate of lifespan.