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Results for “Sirtuin 2”

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PubMed2005

Cerebellar protein expression in three different mouse strains and their relevance for motor performance.

The present study uses a proteomic approach to link motor function to cerebellar protein expression in 129X1/SvJ, C57BL/6J and nNOS WT mice. Poor performance on the Rota rod, the standard test for motor coordination, was detected in 129X1/SvJ mice. No gross impairments of neurological, cognitive and behavioural functions were observed. Identification and quantification of 48 proteins revealed reduced expression of calbindin, septin 5 and syntaxin binding protein 1 in 129X1/SvJ. In nNos WT glucose-6-phosphate 1 dehydrogenase X was decreased whereas dihydropyrimidinase-related protein-4 was increased. In C57BL/6J stress-70 protein, alpha enolase, NAD-dependent deacetylase sirtuin 2, septin 2, dihydropyrimidinase-related protein-2 and brain derived neurotrophic factor showed elevated levels. Neurological examination, Rota rod test, Morris Water Maze, Multiple-T-Maze, Open field and Elevated plus-maze were employed to study motor, cognitive and behavioural function. Mice were sacrificed and cerebellar tissue was homogenized. Proteins were extracted and separated on two-dimensional gel electrophoresis with subsequent in-gel digestion followed by mass spectrometrical analysis of peptides (MALDI-TOF/TOF-TOF). Quantification of spots was carried out by specific software. A strong association of impaired motor function with altered cerebellar protein expression of calbindin, septin 5 and syntaxin binding protein 1in 129X1/SvJ was observed and is in agreement with previous observations of motor deficiencies in a calbindin knock-out mouse. These results have to be taken into account when using 129X1/SvJ for biochemical, toxicological or gene targeting experiments as well as when studying the above-mentioned proteins or corresponding pathways and cascades in this mouse strain.

Animals↗
PubMed2002

Acetylation and accessibility of rDNA chromatin in Saccharomyces cerevisiae in (Delta)top1 and (Delta)sir2 mutants.

The insertion of reporter genes in the ribosomal DNA (rDNA) locus of Saccharomyces cerevisiae causes their transcriptional repression. This kind of transcriptional silencing depends on proteins such as Sir2p and Top1p, and has been shown to be mediated by chromatin. While Sir2p modifies nucleosomes directly through its histone deacetylase activity, little is known about changes in the chromatin structure that occur at the rDNA locus when TOP1 is deleted. Here, we show that the absence of Top1p causes increased histone acetylation at the rDNA locus. Moreover, rDNA chromatin becomes more accessible in a similar manner in both top1 and sir2 mutant strains.

Acetylation↗
PubMed2001

The impact energy metabolism and genome maintenance have on longevity and senescence: lessons from yeast to mammals.

The phenomenon that caloric restriction increases life span in a variety of species from yeast to mice has been the focus of much interest. Recent observations suggest that a protein important for heterochromatin formation, Sir2, is central for caloric restriction-induced longevity in lower organisms. Interestingly, Sir2 is also capable of repairing DNA double-strand breaks by nonhomologous end joining which may be important, along with proteins that repair breaks by recombinational repair, for minimizing the age-related deleterious effects of DNA damage induced by oxygen by-products of metabolism. I propose that competition between these two distinct functions could influence longevity and the onset of senescence. In addition, sequence and functional similarities between Sir2 and other chromatin metabolism proteins present the possibility that genetic components for longevity and senescence are conserved from yeast to mammals.

Aging↗
PubMed1996

A deubiquitinating enzyme interacts with SIR4 and regulates silencing in S. cerevisiae.

The SIR2, SIR3, and SIR4 proteins are required for silencing of transcription at the silent mating type loci and at telomeres in yeast. Using protein affinity chromatography, we show that SIR2, SIR3, and two proteins of 69 and 110 kDa tightly associate with SIR4. Surprisingly, the 110 kDa SIR4-binding protein is identical to UBP3, one of several previously described yeast enzymes that deubiquitinate target proteins. Deletion of the UBP3 gene results in markedly improved silencing of genes inserted either near a telomere or at one of the silent mating type loci, indicating that UBP3 is an inhibitor of silencing. We discuss possible roles for UBP3 in controlling the activity or assembly of the SIR protein complex.

Amino Acid Sequence↗
PubMed1999

Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity.

The Sir2 protein mediates gene silencing and repression of recombination at the rDNA repeats in budding yeast. Here we show that Sir2 executes these functions as a component of a nucleolar complex designated RENT (regulator of nucleolar silencing and telophase exit). Net1, a core subunit of this complex, preferentially cross-links to the rDNA repeats, but not to silent DNA regions near telomeres or to active genes, and tethers the RENT complex to rDNA. Net1 is furthermore required for rDNA silencing and nucleolar integrity. During interphase, Net1 and Sir2 colocalize to a subdomain within the nucleous, but at the end of mitosis a fraction of Sir2 leaves the nucleolus and disperses as foci throughout the nucleus, suggesting that the structure of rDNA silent chromatin changes during the cell cycle. Our findings suggest that a protein complex shown to regulate exit from mitosis is also involved in gene silencing.

Base Sequence↗
PubMed1999

Pch2 links chromatin silencing to meiotic checkpoint control.

The PCH2 gene of Saccharomyces cerevisiae is required for the meiotic checkpoint that prevents chromosome segregation when recombination and chromosome synapsis are defective. Mutation of PCH2 relieves the checkpoint-induced pachytene arrest of the zip1, zip2, and dmc1 mutants, resulting in chromosome missegregation and low spore viability. Most of the Pch2 protein localizes to the nucleolus, where it represses meiotic interhomolog recombination in the ribosomal DNA, apparently by excluding the meiosis-specific Hop1 protein. Nucleolar localization of Pch2 depends on the silencing factor Sir2, and mutation of SIR2 also bypasses the zip1 pachytene arrest. Under certain circumstances, Sir3-dependent localization of Pch2 to telomeres also provides checkpoint function. These unexpected findings link the nucleolus, chromatin silencing, and the pachytene checkpoint.

Cell Cycle Proteins↗
PubMed1999

MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.

The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair.

Ataxia Telangiectasia↗
PubMed1999

An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing.

Despite its conservation in organisms from bacteria to human and its general requirement for transcriptional silencing in yeast, the function of the Sir2 protein is unknown. Here we show that Sir2 can transfer labeled phosphate from nicotinamide adenine dinucleotide to itself and histones in vitro. A modified form of Sir2, which results from its automodification activity, is specifically recognized by anti-mono-ADP-ribose antibodies, suggesting that Sir2 is an ADP-ribosyltransferase. Mutation of a phylogenetically invariant histidine residue in Sir2 abolishes both its enzymatic activity in vitro and its silencing functions in vivo. However, the mutant protein is associated with chromatin and other silencing factors in a manner similar to wild-type Sir2. These findings suggest that Sir2 contains an ADP-ribosyltransferase activity that is essential for its silencing function.

Amino Acid Sequence↗
PubMed2001

Crystal structure of a SIR2 homolog-NAD complex.

The SIR2 protein family comprises a novel class of nicotinamide-adenine dinucleotide (NAD)-dependent protein deacetylases that function in transcriptional silencing, DNA repair, and life-span extension in Saccharomyces cerevisiae. Two crystal structures of a SIR2 homolog from Archaeoglobus fulgidus complexed with NAD have been determined at 2.1 A and 2.4 A resolutions. The structures reveal that the protein consists of a large domain having a Rossmann fold and a small domain containing a three-stranded zinc ribbon motif. NAD is bound in a pocket between the two domains. A distinct mode of NAD binding and an unusual configuration of the zinc ribbon motif are observed. The structures also provide important insights into the catalytic mechanism of NAD-dependent protein deacetylation by this family of enzymes.

Amino Acid Sequence↗
PubMed2001

Silenced chromatin is permissive to activator binding and PIC recruitment.

Chromatin is thought to repress transcription by limiting access of the DNA to transcription factors. Using a yeast heat shock gene flanked by mating-type silencers as a model system, we find that repressive, SIR-generated heterochromatin is permissive to the constitutive binding of an activator, HSF, and two components of the preinitiation complex (PIC), TBP and Pol II. These factors cohabitate the promoter with Sir silencing proteins and deacetylated nucleosomal histones. The heterochromatic HMRa1 promoter is also occupied by TBP and Pol II, suggesting that SIR regulates gene expression not by restricting factor access to DNA but rather by blocking a step downstream of PIC recruitment. Interestingly, activation of silent promoter chromatin occurs in the absence of histone displacement and without change in histone acetylation state.

Chromatin↗
PubMed2001

hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.

DNA damage-induced acetylation of p53 protein leads to its activation and either growth arrest or apoptosis. We show here that the protein product of the gene hSIR2(SIRT1), the human homolog of the S. cerevisiae Sir2 protein known to be involved in cell aging and in the response to DNA damage, binds and deacetylates the p53 protein with a specificity for its C-terminal Lys382 residue, modification of which has been implicated in the activation of p53 as a transcription factor. Expression of wild-type hSir2 in human cells reduces the transcriptional activity of p53. In contrast, expression of a catalytically inactive hSir2 protein potentiates p53-dependent apoptosis and radiosensitivity. We propose that hSir2 is involved in the regulation of p53 function via deacetylation.

Animals↗