Fluorescence in situ hybridization and chromosomal organization of the human Sirtuin 7 gene
ABSTRACT Sirtuin 7 (SIRT7) is a member of the sirtuin family of protein deacetylases and is, therefore, a derivative of yeast Silent information regulator 2 (SIR2). SIR2 and its mammalian orthologs play an important role in epigenetic gene silencing, DNA recombination, cellular differentiation and metabolism, and the regulation of aging. In contrast to most sirtuins, SIRT7 does not exert characteristic NAD+-dependent deacetylase activity. We have isolated and characterized the human Sirt7 genomic sequence, which spans a region of 6.2 kb and which has one single genomic locus. Determination of the exon/intron splice junctions found the full-length SIRT7 protein to consist of 10 exons ranging in size from 71 bp (exon 4) to 237 bp (exon 7). The human Sirt7 open reading frame encodes a 400-aa protein with a predictive molecular weight of 44.9 kDa and an isoelectric point of 9.80. Characterization of the 5' flanking genomic region, which precedes the Sirt7 open reading frame, revealed a TATA- and CCAAT-box less promoter that lacks CpG islands. A number of AML-1 and GATA-x transcription factor binding sites were found, which remain to be further evaluated experimentally. Fluorescence in situ hybridization analysis localized the human Sirt7 gene to chromosome 17q25.3; a region which is frequently affected by chromosomal alterations in acute leukemias and lymphomas. Human SIRT7 appears to be most predominantly expressed in the blood and in CD33+ myeloid bone marrow precursor cells, while the lowest levels are found in the ovaries and skeletal muscle. Functional characteristics of SIRT7 are essentially unknown at present and remain to be further elucidated.
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ABSTRACT: Sirt7 is a member of the mammalian sirtuin family consisting of 7 genes, Sirt1 to Sirt7, which all share a homology to the founding family member, the yeast Sir2 gene. Most sirtuins are supposed to act as histone/protein deacetylases, which use oxidized NAD in a sirtuin-specific, 2-step deacetylation reaction. To begin to decipher the biological role of Sirt7, we inactivated the Sirt7 gene in mice. Sirt7-deficient animals undergo a reduction in mean and maximum lifespans and develop heart hypertrophy and inflammatory cardiomyopathy. Sirt7 mutant hearts are also characterized by an extensive fibrosis, which leads to a 3-fold increase in collagen III accumulation. We found that Sirt7 interacts with p53 and efficiently deacetylates p53 in vitro, which corresponds to hyperacetylation of p53 in vivo and an increased rate of apoptosis in the myocardium of mutant mice. Sirt7-deficient primary cardiomyocytes show a approximately 200% increase in basal apoptosis and a significantly diminished resistance to oxidative and genotoxic stress suggesting a critical role of Sirt7 in the regulation of stress responses and cell death in the heart. We propose that enhanced activation of p53 by lack of Sirt7-mediated deacetylation contributes to the heart phenotype of Sirt7 mutant mice.Circulation Research 04/2008; 102(6):703-10. DOI:10.1161/CIRCRESAHA.107.164558 · 11.09 Impact Factor
Article: Sirtuin inhibitors[Show abstract] [Hide abstract]
ABSTRACT: The sirtuin family of deacetylase enzymes comprises seven proteins (SIRT1-7) that are dependent on NAD(+) for their activity. Three proteins are located in the nucleus, three in the mitochondria and only one is predominantly cytoplasmic. Caloric restriction and oxidative stress generally up-regulate their expression. SIRT1, the orthologue of yeast Sir2, is the mammalian sirtuin that has been most extensively studied to date. Among other targets, SIRT1 down-regulates the activity of the nuclear transcription factor p53, being this related with an increase in lifespan and cell survival associated to stress resistance. Because sirtuin modulation could have beneficial effects on several human diseases, there is a growing interest in the discovery and development of small molecules that modify its activity. This review will be focused on sirtuin inhibitors. Several specific inhibitors of SIRT1 have been described. These compounds could be mainly useful for the treatment of cancers by increasing p53 activity that stops the formation of tumours and induces apoptosis. A p53-independent massive induction of apoptosis has been also described for one inhibitor. In addition, a potent and selective SIRT2 inhibitor that ameliorates the alpha-synuclein fibril formation in Parkinson disease has been proposed to treat this kind of neurodegenerative disease.Expert Opinion on Therapeutic Patents 04/2009; 19(3):283-94. DOI:10.1517/13543770902755111 · 3.44 Impact Factor
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ABSTRACT: Human SIRT3 gene contains an intronic VNTR enhancer. A T > C transition occurring in the second repeat of each VNTR allele implies the presence/absence of a putative GATA binding motif. A partially overlapping AP-1 site, not affected by the transition, was also identified. Aims of the present study were: 1) to verify if GATA and AP-1 sites could bind GATA2 and c-Jun/c-Fos factors, respectively; 2) to investigate whether such sites modulate the enhancer activity of the SIRT3-VNTR alleles. DAPA assay proved that GATA2 and c-Jun/c-Fos factors are able to bind the corresponding sites. Moreover, co-transfection experiments showed that the over-expression of GATA2 and c-Jun/c-Fos factors boosts the VNTR enhancer activity in an allelic-specific way. Furthermore, we established that GATA2 and c-Jun/c-Fos act additively in modulating the SIRT3-VNTR enhancer function. Therefore, GATA2 and AP-1 are functional sites and the T S> C transition of the second VNTR repeat affects their activity.Moleculer Cells 09/2009; 28(2):87-92. DOI:10.1007/s10059-009-0110-3 · 2.24 Impact Factor