Silent information regulator protein

SIR proteins have been identified in many screens, and have historically been known as SIR (sterile), CMT (sterile suppressor) according to which screen led to their identification. Ultimately, the name SIR had the most staying power, because it most accurately describes the function of the encoded proteins. One of the early yeast screens to identify SIR genes was performed by Anita Hopper and Benjamin Hall, who screened with mutagenesis for alleles that allow sporulation in a normally sporulation-deficient heterothallic α/α (ho/ho MATα/MATα). Their screen identified a mutation in a novel gene that was not linked to HO that allowed the α/α diploid to sporulate, as if it were an α/a diploid, and inferred that the mutation affected a change in mating type by an HO-independent mechanism. Later, it was discovered at the CMT allele identified by Hopper & Hall did not cause a mating type conversion at the MAT locus, but rather allowed the expression of cryptic mating type genes that are silenced in wild-type yeast. In the same year that Haber & demonstrated that the cmt mutant restores sporulation by de-repressing hidden mating type loci, two other groups published screens for genes involved in the regulation of silent mating type cassettes. 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. In fact, the genes that are now referred to as SIR1-4 have at one time been referred to as MAR, CMT or STE according to the screen that identified the mutants. Although Klar, Hartwell and Hopper identified mutations in SIR genes and applied other names to the genes before Rine performed his screen, the SIR name was eventually adopted because Rine eventually identified the most complete set of functionally related genes (SIR1-4), and because the work by Rine and Herskowitz most accurately described the function of the SIR family genes. Later it would be shown that in yeast and in higher organisms, SIR proteins are important for transcriptional regulation of many chromatin domains. ==Molecular mechanism==

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. At the rDNA locus, SIR proteins are thought to primarily be important for repressing recombination between rDNA repeats rather than for suppressing transcription. Transcriptional silencing in budding yeast In transcriptional silencing, SIR2,3,4 are required in stoichiometric amounts to silence specific chromosomal regions. 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. Rap1 contains a Sir3-binding domain that recruits SIR3 to the silencers. Once at the silencers, Sir3 recruits Sir4-Sir2 dimers to the chromatin nucleation site. 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. Specifically, if an inducible promoter is induced inside a silent chromatin domain, it can achieve ~200x increase in expression levels with little detectable change in covalent histone modifications. 'priming' the nucleosome for chromatin packaging by the SIR3 component of the complex. Stabilization of rDNA in budding yeast Beyond its canonical role in the SIR complex, SIR2 also plays a role in rDNA repression. As part of the cell's regulation mechanism, rDNA repeats are excised from the chromosome so they cannot be expressed. SIR2 forms a complex with NET1 (a nuclear protein) and CDC14 (a phosphatase) to form the regulator of nucleolar silencing and telophase (RENT) complex. SIR4 SIR4 is involved in scaffolding the assembly of silenced chromatin. It binds to DNA with high affinity, but low specificity. It is most stable when co-expressed with SIR2, but neither SIR2 nor SIR3 are required for it to operate at the telomeres. Each half of the SIR4 protein has distinct responsibilities in heterochromatin spreading. SIR4's N-terminus is required for telomeric silencing, but not for homothallic mating-type (HM) silencing. Conversely, its C-terminus supports HM but not telomeric repression. The N-terminus is positively charged and can be recruited to the telomeric repression site by SIR1 and YKU80. The C-terminus contains the coiled-coil region, which interacts with SIR3 in the heterotrimeric SIR complex and can also interact with RAP1 and YKU70 for recruitment to the telomeric region of the chromosome. The C-terminus also contains the SIR2-interacting domain (SID), where SIR4 can bind to the extended N-terminus of SIR2. SIR2 can catalyze reactions without being bound to SIR4, but SIR2's catalytic activity is enhanced when interacting with SIR4. ==Conservation==

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. == See also ==