Sirtuin 7

NAD-dependent deacetylase sirtuin 7 is an enzyme that in humans is encoded by the SIRT7 gene.[5][6][7] SIRT7 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

SIRT7
Identifiers
AliasesSIRT7, SIR2L7, sirtuin 7
External IDsOMIM: 606212 MGI: 2385849 HomoloGene: 56152 GeneCards: SIRT7
Orthologs
SpeciesHumanMouse
Entrez

51547

209011

Ensembl

ENSG00000187531

ENSMUSG00000025138

UniProt

Q9NRC8

Q8BKJ9

RefSeq (mRNA)

NM_016538

NM_153056
NM_001363439

RefSeq (protein)

NP_057622

NP_694696
NP_001350368

Location (UCSC)Chr 17: 81.91 – 81.92 MbChr 11: 120.51 – 120.52 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

SIRT7 facilitates the transcription of DNA by DNA polymerase I, DNA polymerase II, and DNA polymerase III.[8]

In humans cells, SIRT7 has only been shown to interact with two other molecules: RNA polymerase I (RNA Pol I) and upstream binding factor (UBF).[6] SIRT7 is localized to the nucleolus and interacts with RNA Pol I. Chromatin immunoprecipitation studies demonstrate that SIRT7 localizes to rDNA, and coimmunoprecipitation shows that SIRT7 binds RNA Pol I. In addition SIRT7 interacts with UBF, a major component of the RNA Pol I initiation complex.[9] It is not known whether or not SIRT7 is modifying RNA Pol I and/or UBF, and if so, what those modifications are.

SIRT7 is expressed more in metabolically active tissues, such as liver and spleen, and less in non-proliferating tissues, such as heart and brain.[6] Furthermore, it has been shown that SIRT7 is necessary for rDNA transcription. Knock down of SIRT7 in HEK293 cells resulted in decreased rRNA levels. This same study found that this SIRT3 knockdown decreased the amount of RNA Pol I associated with rDNA, suggesting that SIRT7 may be required for rDNA transcription. Knock down SIRT7 led to reduced RNA Pol I levels, but RNA Pol I mRNA levels did not change. This suggests that SIRT7 plays a crucial role in connecting the function of chromatin remodeling complexes to RNA Pol I machinery during transcription.[10]

SIRT7 may help attenuate DNA damage and thereby promoting cellular survival under conditions of genomic stress.[11] Ribosomal DNA (rDNA) is more vulnerable to DNA damage than DNA elsewhere in the genome such than rDNA instability can lead to cellular senescence, and thus to senescence-associated secretory phenotype.[12] SIRT7 localizes to rDNA thereby protecting against rDNA instability and cellular senescence.[12]

DNA repair

Depletion of SIRT7 results in impaired repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining (NHEJ).[13] DSBs are one of the most significant types of DNA damage leading to genome instability. SIRT7 is recruited to DSBs where it specifically deacylates histone H3 at lysine 18. This affects the focal accumulation of the DNA damage response factor 53BP1, a protein that promotes NHEJ by protecting DNA from end resection.[13][14]

SIRT7 overexpression has been shown to improve efficiency of NHEJ by 1.5-fold, and of homologous recombination by 2.8-fold.[15]

Accelerated aging

Sirt7 mutant mice show phenotypic and molecular features of accelerated aging.[13] These features include premature curvature of the spine, reduced weight and fat content, compromised hematopoietic stem cell function and leukopenia, and multiple organ dysfunction.[13][14]

Clinical relevance

This gene has been found to be involved in maintenance of oncogenic transformation.[16]

References
  1. GRCh38: Ensembl release 89: ENSG00000187531 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000025138 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Frye RA (Jul 2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochemical and Biophysical Research Communications. 273 (2): 793–98. doi:10.1006/bbrc.2000.3000. PMID 10873683.
  6. Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L (May 2006). "Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription". Genes & Development. 20 (9): 1075–80. doi:10.1101/gad.1399706. PMC 1472467. PMID 16618798.
  7. "Entrez Gene: SIRT7 sirtuin (silent mating type information regulation 2 homolog) 7 (S. cerevisiae)".
  8. Blank MF, Grummt I (2017). "The seven faces of SIRT7". Transcription. 8 (2): 67–74. doi:10.1080/21541264.2016.1276658. PMC 5423475. PMID 28067587.
  9. Grob A, Roussel P, Wright JE, McStay B, Hernandez-Verdun D, Sirri V (Feb 2009). "Involvement of SIRT7 in resumption of rDNA transcription at the exit from mitosis". Journal of Cell Science. 122 (Pt 4): 489–98. doi:10.1242/jcs.042382. PMC 2714433. PMID 19174463.
  10. Tsai YC, Greco TM, Boonmee A, Miteva Y, Cristea IM (Feb 2012). "Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription". Molecular & Cellular Proteomics. 11 (2): M111.015156. doi:10.1074/mcp.M111.015156. PMC 3277772. PMID 22147730.
  11. Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, Haynes CM, Chen D (Mar 2015). "Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging". Science. 347 (6228): 1374–77. Bibcode:2015Sci...347.1374M. doi:10.1126/science.aaa2361. PMC 4447312. PMID 25792330.
  12. Paredes S, Angulo-Ibanez M, Tasselli L, Chua KF (2018). "The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability". Journal of Biological Chemistry. 293 (28): 11242–11250. doi:10.1074/jbc.AC118.003325. PMC 6052228. PMID 29728458.
  13. Vazquez BN, Thackray JK, Simonet NG, Kane-Goldsmith N, Martinez-Redondo P, Nguyen T, Bunting S, Vaquero A, Tischfield JA, Serrano L (2016). "SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair". EMBO J. 35 (14): 1488–503. doi:10.15252/embj.201593499. PMC 4884211. PMID 27225932.
  14. Vazquez BN, Thackray JK, Serrano L (2017). "Sirtuins and DNA damage repair: SIRT7 comes to play". Nucleus. 8 (2): 107–15. doi:10.1080/19491034.2016.1264552. PMC 5403131. PMID 28406750.
  15. Mao Z, Hine C, Tian X, Seluanov A, Gorbunova V (2011). "SIRT6 promotes DNA repair under stress by activating PARP1". Science. 332 (6036): 1443–1446. Bibcode:2011Sci...332.1443M. doi:10.1126/science.1202723. PMC 5472447. PMID 21680843.
  16. Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, Tennen RI, Paredes S, Young NL, Chen K, Struhl K, Garcia BA, Gozani O, Li W, Chua KF (Jul 2012). "SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation" (PDF). Nature. 487 (7405): 114–18. Bibcode:2012Natur.487..114B. doi:10.1038/nature11043. PMC 3412143. PMID 22722849.

Further reading
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