SIRT7

Description

The SIRT7 (sirtuin 7) is a protein-coding gene located on chromosome 17.

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

== Function == SIRT7 facilitates the transcription of DNA by DNA polymerase I, DNA polymerase II, and DNA polymerase III. In human cells, SIRT7 has only been shown to interact with two other molecules: RNA polymerase I (RNA Pol I) and upstream binding factor (UBF). 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. 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. 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 SIRT7 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.

SIRT7 is a NAD-dependent protein-lysine deacylase that can act as both a deacetylase or deacylase (desuccinylase, depropionylase, deglutarylase and dedecanoylase), depending on the context. It specifically mediates deacetylation of histone H3 at 'Lys-18' (H3K18Ac). In contrast to other histone deacetylases, SIRT7 displays a strong preference for H3K18Ac, a histone mark directly linked to gene expression control. H3K18Ac is primarily found around the transcription start site of genes and has been linked to the activation of nuclear hormone receptors; therefore, SIRT7 acts as a transcription repressor. Hypoacetylation of H3K18 has been reported as a marker of malignancy in various cancers and appears to maintain the transformed phenotype of cancer cells. SIRT7 can also deacetylate histone H3 at 'Lys-36' (H3K36Ac) within nucleosomes. It also mediates deacetylation of non-histone proteins, including ATM, CDK9, DDX21, DDB1, FBL, FKBP5/FKBP51, GABPB1, RAN, RRP9/U3-55K and POLR1E/PAF53. SIRT7 is enriched in the nucleolus, where it stimulates the transcription activity of the RNA polymerase I complex. It achieves this by deacetylating the RNA polymerase I subunit POLR1E/PAF53, promoting the association of RNA polymerase I with the rDNA promoter and coding regions. In response to metabolic stress, SIRT7 is released from nucleoli, leading to hyperacetylation of POLR1E/PAF53 and decreased RNA polymerase I transcription. SIRT7 is required to restore ribosomal RNA (rRNA) transcription upon exiting mitosis. It promotes pre-ribosomal RNA (pre-rRNA) cleavage at the 5'-terminal processing site by deacetylating RRP9/U3-55K, a core subunit of the U3 snoRNP complex. SIRT7 mediates 'Lys-37' deacetylation of Ran, thereby regulating the nuclear export of the NF-kappa-B subunit RELA/p65. SIRT7 acts as a regulator of DNA damage repair by deacetylating ATM during the late stages of the DNA damage response, promoting ATM dephosphorylation and deactivation. It suppresses the activity of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes by deacetylating DDB1, which prevents the interaction between DDB1 and CUL4 (CUL4A or CUL4B). SIRT7 activates RNA polymerase II transcription by deacetylating CDK9, promoting 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. It deacetylates FBL, promoting the histone-glutamine methyltransferase activity of FBL. SIRT7 acts as a regulator of mitochondrial function by catalyzing the deacetylation of GABPB1. It regulates Akt/AKT1 activity by deacetylating FKBP5/FKBP51. SIRT7 is required to prevent R-loop-associated DNA damage and transcription-associated genomic instability by deacetylating and subsequently activating DDX21, overcoming R-loop-mediated stalling of RNA polymerases. In addition to its protein deacetylase activity, SIRT7 also acts as a protein-lysine deacylase. It functions as a protein depropionylase by depropionylating Osterix (SP7), regulating bone formation by osteoblasts. SIRT7 acts as a histone deglutarylase by deglutarylating histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting the dissociation of the H2A-H2B dimers from nucleosomes. It acts as a histone desuccinylase. In response to DNA damage, SIRT7 is recruited to DNA double-strand breaks (DSBs) and catalyzes the desuccinylation of histone H3 on 'Lys-122' (H3K122succ), promoting chromatin condensation and DSB repair. SIRT7 also promotes DSB repair by promoting H3K18Ac deacetylation, regulating non-homologous end joining (NHEJ). Along with its role in DNA repair, SIRT7 is required for chromosome synapsis during prophase I of female meiosis by catalyzing H3K18Ac deacetylation. It is involved in the transcriptional repression of LINE-1 retrotransposon via H3K18Ac deacetylation, and promotes their association with the nuclear lamina. SIRT7 is required to stabilize ribosomal DNA (rDNA) heterochromatin and prevent cellular senescence induced by rDNA instability. It acts as a negative regulator of SIRT1 by preventing autodeacetylation of SIRT1, restricting SIRT1 deacetylase activity. SIRT7 interacts with UBTF and the RNA polymerase I complex. It interacts with components of the B-WICH complex, such as MYBBP1A, SMARCA5/SNF2H and BAZ1B/WSTF. SIRT7 interacts with ELK4, leading to stabilization at target promoters for H3K18Ac deacetylation. It interacts with histone H2A and/or histone H2B. SIRT7 interacts with DNMT1 and SIRT1.

SIRT7 is also known as SIR2L7.

Associated Diseases

WES Whole Exome Sequencing