Disease relevance of SIR2

• Short-chain fatty acid activation by acyl-coenzyme A synthetases requires SIR2 protein function in Salmonella enterica and Saccharomyces cerevisiae [1].
• Splitomicin (1) and 41 analogues were prepared and evaluated in cell-based Sir2 inhibition and toxicity assays and an in vitro Sir2 inhibition assay [2].
• Furthermore, Sir2 expression was increased significantly in hearts from dogs with heart failure induced by rapid pacing superimposed on stable, severe hypertrophy [3].
• Unlike yeast sir2 mutants, our sir2alpha null ES cells had normal sensitivity to insults such as ionizing radiation and heat shock, and they were able to silence invading retroviruses normally [4].

High impact information on SIR2

• Unlike SIR3 and SIR4, the SIR2 gene is highly conserved in organisms ranging from archaea to humans [5].
• The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast [6].
• Lack of Sir2 along with calorie restriction and/or mutations in the yeast AKT homolog, Sch9, or Ras pathways causes a dramatic chronological life-span extension [7].
• Sir2 couples deacetylation to NAD hydrolysis and the synthesis of a metabolite, O-acetyl-ADP-ribose (AAR), but the functional significance of NAD hydrolysis or AAR, if any, is unknown [8].
• Inactivation of Sir2 causes uptake and catabolism of ethanol and upregulation of many stress-resistance and sporulation genes [7].

Biological context of SIR2

• The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability [9].
• A deletion of SIR2 uniquely rescued both the DNA synthesis defect of the cdc6-4 mutant and its severe plasmid instability phenotype for many origins [10].
• We describe two novel classes of SIR2 mutations specific to either HM/telomere or rDNA silencing [11].
• The yeast SIR2 gene maintains inactive chromatin domains required for transcriptional repression at the silent mating-type loci and telomeres [12].
• Furthermore, using an in vivo plasmid rejoining assay, we demonstrate that SIR2, SIR3 and SIR4, three genes shown previously to function in TPE, are essential for Ku-dependent DSB repair [13].

Anatomical context of SIR2

• Human SIR2A and yeast SIR2 proteins restored growth of SIR2-deficient S. enterica on acetate and propionate, suggesting that eukaryotic cells may also use SIR2 proteins to control the synthesis of acetyl-CoA by the level of acetylation of acetyl-CoA synthetases [1].
• Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells [14].
• SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria [15].
• Furthermore, sirtuin1 (SIRT1), the mammalian ortholog of the life-extending yeast gene silent information regulator 2 (SIR2), was proposed to be involved in the molecular mechanisms linking lifespan to adipose tissue [16].
• Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes [17].

Associations of SIR2 with chemical compounds

• In rDNA, SIR2 is required for a more closed chromatin structure in two regions: SRR1, the major SIR-Responsive Region in the non-transcribed spacer, and SRR2, in the 18S rRNA coding region [12].
• The presence of Sir2p at both the spacer of the rDNA repeat and at telomeres is confirmed by formaldehyde cross-linking and immunoprecipitation with anti-Sir2p antibodies [18].
• Sir2p is a TSA-resistant HDAC that mediates yeast silencing [19].
• We propose a model in which two components of the NAD(+) salvage pathway, Pnc1p and Npt1p, function together in recycling the nuclear nicotinamide generated by Sir2p deacetylase activity back into NAD(+) [20].
• Consistent with this idea, growth of a quintuple sir2 hst1 hst2 hst3 hst4 mutant strain of the yeast Saccharomyces cerevisiae on acetate or propionate was severely impaired [1].

Physical interactions of SIR2

• At HM loci and telomeres, Sir2p forms a complex with Sir3p and Sir4p [11].
• Mutations in the HDB (RPD3) histone deacetylase complex paradoxically increased rDNA silencing by a SIR2-dependent, SIR3-independent mechanism [21].
• We found that yeast extracts contained a SIR2/SIR4 complex that was associated with little or no SIR3 [22].

Regulatory relationships of SIR2

• Although SIR2-dependent processes are enhanced by additional NPT1, steady-state NAD(+) levels and NAD(+)/NADH ratios remain unaltered [23].
• Distribution of a limited Sir2 protein pool regulates the strength of yeast rDNA silencing and is modulated by Sir4p [24].
• The short life span of a sir2 mutant also reveals a direct failure to repress recombination generated by the Fob1p-mediated replication block in the rDNA [25].
• We previously demonstrated that SIR2 also acts to repress mitotic and meiotic recombination between the tandem ribosomal RNA gene array (rDNA) [12].
• Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity [26].

Other interactions of SIR2

• Silencing by GBD/RAP1 hybrids, like normal silencing at HMR, requires the trans-acting factors SIR2, SIR3, and SIR4 [27].
• The unexpected nucleolar localization of Sir2p and Sir3p correlates with observed effects of sir mutations on rDNA stability and yeast longevity, defining a new site of action for silent information regulatory factors [18].
• Finally, bioinformatic analyses indicate that the yeast HDACs RPD3, SIR2, and HDA1 play distinct roles in regulating genes involved in cell cycle progression, amino acid biosynthesis, and carbohydrate transport and utilization, respectively [19].
• In addition, the life span of dna2 mutants is extended by expression of an additional copy of SIR2 or by deletion of FOB1, which also increase wild-type life span [28].
• Both NPT1 and SIR2 provide resistance against heat shock, demonstrating that these genes act in a more general manner to promote cell survival [23].

Analytical, diagnostic and therapeutic context of SIR2

• SIR2 deletion shortened life span but did not prevent extension of life span by caloric restriction [29].
• Chromatin immunoprecipitation revealed that Sir2 localizes to the lacO region in response to activation of the dicentric chromosome [30].

References