User:ImperialSquash/SIR proteins

SIR2

SIR2 is an NAD-dependent lysine deacetylase. It was the first-discovered member of the sirtuin protein family and is highly conserved, with homologs found in organisms ranging from humans to bacteria and archaea. It interacts with a variety of protein substrates, but does not exhibit strong affinity for DNA, chromatin, or other silencer-binding factors. Instead, it relies on other SIR proteins to find its appropriate silencing target.

In the SIR protein complex, SIR2 removes acetyl groups from the lysine on histone tails H3 and H4, '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 ribosomal DNA (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. The RENT complex sequesters excised rDNA in 'extrachromosomal circles,' preventing recombination. Accumulation of these circles has been linked to premature aging. SIRT2, SIR2's human analog, has also been linked to age-related disease.

SIR3

SIR3 is principally involved in heterochromatin spreading, the silencing activity of the SIR protein complex. When overexpressed, SIR3 leads to spreading beyond the normal nucleation site. SIR3 can continue to operate at very low levels of SIR2 and SIR4, but not without them. It preferentially binds to unmodified nucleosomes (no acetylation at H4K16 or methylation at H3K79), and relies on SIR2's deacetylation of H4K16 to enhance silencing. H3K79 methylation by DOT1 methyltransferase inhibits SIR3, resulting in an unsilenced chromatin region. SIR3 is recruited to a target sequence by RAP1 or ABF1.

SIR4

SIR2 homodimer (green) in complex with SIR4's (purple) SIR2-interacting domain (SID; yellow)

SIR4 is involved in scaffolding in 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 hetero trimeric 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 this interaction enhances SIR2's catalytic activity.