Alternative titles; symbols
HGNC Approved Gene Symbol: SIRT7
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,911,939-81,918,176 (from NCBI)
SIRT7 belongs to the sirtuin family of genes that share homology with yeast Sir2. Most sirtuins act as histone/protein deacetylases, and sirtuins are implicated in several critical cellular processes, including differentiation, proliferation, apoptosis, metabolism, and senescence (summary by Vakhrusheva et al., 2008).
By searching an EST database with SIRT4 (604482) as the probe, Frye (2000) obtained cDNAs encoding SIRT6 (606211) and SIRT7. The deduced 400-amino acid SIRT7 protein belongs to sirtuin class IV, which is not present in prokaryotes.
Voelter-Mahlknecht et al. (2006) reported that the deduced 400-amino acid SIRT7 protein has a calculated molecular mass of 44.9 kD. The sirtuin catalytic domain is located between residues 107 and 278. In silico analysis suggested that SIRT7 is highly expressed in blood, CD33 (159590)-positive myeloid bone marrow precursor cells, and pancreas, with lowest expression in ovary and skeletal muscle.
By Northern blot analysis, Ford et al. (2006) found that Sirt7 was expressed in all mouse tissues examined except skeletal muscle, with highest expression in liver. Endogenous human SIRT7 colocalized with RNA polymerase I (pol I; see 602000) and UBF (600673) in nucleoli. During M phase, when nucleoli disintegrate, SIRT7 was not retained at the nucleolus organizer region, but remained bound to the condensed mitotic chromatin.
Ford et al. (2006) found that SIRT7 associated with active rRNA genes (rDNA) and histones. Overexpression of SIRT7 increased pol I-mediated transcription, whereas knockdown of SIRT7 or inhibition of its catalytic activity resulted in decreased association of pol I with rDNA and reduced pol I transcription. Depletion of SIRT7 stopped cell proliferation and triggered apoptosis.
Using primary neonatal mouse cardiomyocytes, Vakhrusheva et al. (2008) showed that Sirt7 deacetylated p53 (TP53; 191170) and increased cellular resistance to cytotoxic and oxidative stress. Protein pull-down and immunoprecipitation analyses confirmed a direct interaction between Sirt7 and p53.
Barber et al. (2012) showed that SIRT7 is an NAD(+)-dependent H3K18Ac (acetylated lysine-18 of histone H3; see 602810) deacetylase that stabilizes the transformed state of cancer cells. Genomewide binding studies revealed that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed-specific (ETS) transcription factor ELK4 (600246), and comprises numerous genes with links to tumor suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumor phenotypes and poor prognosis. Barber et al. (2012) found that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Barber et al. (2012) concluded that their work established SIRT7 as a highly selective H3K18Ac deacetylase and demonstrated a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs, and tumor formation in vivo.
Mohrin et al. (2015) identified a regulatory branch of the mitochondrial unfolded protein response (UPR-mt), which is mediated by the interplay of SIRT7 and NRF1 (600879) and is coupled to cellular energy metabolism and proliferation. SIRT7 inactivation caused reduced quiescence, increased mitochondrial protein folding stress, and compromised regenerative capacity of hematopoietic stem cells (HSCs). SIRT7 expression was reduced in aged HSCs, and SIRT7 upregulation improved the regenerative capacity of aged HSCs. Mohrin et al. (2015) concluded that these findings defined the deregulation of a mitochondrial UPR-mediated metabolic checkpoint as a reversible contributing factor for HSC aging.
Voelter-Mahlknecht et al. (2006) determined that the SIRT7 gene contains 10 exons and spans 6.2 kb. The 5-prime region contains binding sites for AML1 (RUNX1; 151385), GATA (see 305371), CEBPA (116897), and SP1 (189906). The SIRT7 gene contains a number of Alu repeats, predominantly within intron 3.
Frye (2000) stated that the SIRT7 gene maps to the distal end of chromosome 17q. Using FISH, Voelter-Mahlknecht et al. (2006) mapped the SIRT7 gene to chromosome 17q25.3.
Vakhrusheva et al. (2008) found that Sirt7 +/- mice had no obvious phenotype, whereas Sirt7 -/- mice showed various signs of age-related changes and died prematurely. Sirt7 -/- mice developed kyphosis and lost subcutaneous fat early in life, and they showed reduced resistance to stress. The level of Sirt7 fell in aged (23 months old) wildtype hearts, and deletion of Sirt7 resulted in degenerative hypertrophy with strong increase in fibrosis, enhanced accumulation of lipofuscin inclusions, and elevated number of apoptotic cardiomyocytes. In culture, primary Sirt7 -/- cardiomyocytes showed elevated sensitivity to genotoxic and oxidative stress compared with wildtype. Sirt7 -/- cardiomyocytes showed changes in cell signaling associated with hypertrophy and heart failure, including elevated Akt (see 164730) activation and increased expression of Ras (see 190020) and Raf1 (164760). Mutant hearts also showed elevated proapoptotic changes, including increased amount of proapoptotic Fas/Cd95 (TNFRSF6; 134637) protein and acetylated p53 (191170). Vakhrusheva et al. (2008) concluded that enhanced activation of p53 due to lack of Sirt7-mediated deacetylation contributes to the heart phenotype of Sirt7 -/- mice, and that reduced expression of SIRT7 with age may cause age-related changes in the heart.
Barber, M. F., Michishita-Kioi, E., Xi, Y., Tasselli, L., Kioi, M., Moqtaderi, Z., Tennen, R. I., Paredes, S., Young, N. L., Chen, K., Struhl, K., Garcia, B. A., Gozani, O., Li, W., Chua, K. F. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 487: 114-118, 2012. [PubMed: 22722849] [Full Text: https://doi.org/10.1038/nature11043]
Ford, E., Voit, R., Liszt, G., Magin, C., Grummt, I., Guarente, L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20: 1075-1080, 2006. [PubMed: 16618798] [Full Text: https://doi.org/10.1101/gad.1399706]
Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273: 793-798, 2000. [PubMed: 10873683] [Full Text: https://doi.org/10.1006/bbrc.2000.3000]
Mohrin, M., Shin, J., Liu, Y., Brown, K., Luo, H., Xi, Y., Haynes, C. M., Chen, D. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347: 1374-1377, 2015. [PubMed: 25792330] [Full Text: https://doi.org/10.1126/science.aaa2361]
Vakhrusheva, O., Smolka, C., Gajawada, P., Kostin, S., Boettger, T., Kubin, T., Braun, T., Bober, E. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ. Res. 102: 703-710, 2008. [PubMed: 18239138] [Full Text: https://doi.org/10.1161/CIRCRESAHA.107.164558]
Voelter-Mahlknecht, S., Letzel, S., Mahlknecht, U. Fluorescence in situ hybridization and chromosomal organization of the human Sirtuin 7 gene. Int. J. Oncol. 28: 899-908, 2006. [PubMed: 16525639]