SIRT6
GeneName
SIRT6
Summary
SIRT6, also known as SIRT-6, is a 39 kDa NAD+-dependent deacetylase that plays a vital role in chromatin regulation and DNA repair. It is predominantly located in the nucleus, where it associates with chromatin and is involved in various processes including base-excision repair, double-strand break repair, and chromatin remodelling. SIRT6 functions as a transcriptional regulator, influencing gene expression through histone deacetylation and modulating the activity of several proteins involved in cellular processes such as glucose homeostasis and lifespan determination. Its ability to bind to damaged DNA highlights its role as a DNA damage sensor and repair facilitator.
Importance
SIRT6 is relevant to: - Ageing and longevity research due to its involvement in the regulation of lifespan and cellular senescence - Cancer biology through its role in DNA repair mechanisms and chromatin remodelling - Metabolic disorders, as it regulates glucose homeostasis and insulin secretion - Cardiovascular health, given its influence on cardiac muscle cell differentiation and blood vessel branching - Neurobiology, particularly in response to UV-induced stress and the regulation of circadian rhythms
Top Products
For researchers investigating SIRT6, we recommend two excellent primary antibodies. The first is the well-cited polyclonal antibody, Anti-SIRT6 antibody (ab62739), which has garnered 73 citations and is highly regarded for its performance in Western blotting (WB) and immunocytochemistry (ICC). Additionally, we offer the recombinant antibody, Anti-SIRT6 antibody [EPR18463] (ab191385), which has been validated in knockout models and is suitable for a broader range of applications, including WB, ICC, and immunoprecipitation (IP). With 47 citations, this recombinant antibody provides the batch-to-batch consistency that many researchers seek, making it a reliable choice for SIRT6 detection.
Abcam Product Citation Summary
The data indicates that SIRT6 is being extensively studied in various contexts, particularly in human and mouse models. The applications primarily involve Western blotting, with additional methods like ChIP and flow cytometry being used. Research focuses on cellular stress responses, muscle regulation, and the effects of specific compounds on aging and gene regulation.
Abcam Product Citation Table
Domain
The C-terminal disordered region mediates non-specific DNA-binding.
Function
NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging (PubMed:18337721, PubMed:19135889, PubMed:19625767, PubMed:21362626, PubMed:21680843, PubMed:23217706, PubMed:23552949, PubMed:23653361, PubMed:24052263, PubMed:27180906, PubMed:27322069, PubMed:29555651, PubMed:30374165). Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context (PubMed:23552949, PubMed:24052263, PubMed:27322069). Acts as a key histone deacetylase by catalyzing deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56' (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target gene expression of several transcription factors, including NF-kappa-B (PubMed:19625767, PubMed:21362626, PubMed:23892288, PubMed:23911928, PubMed:24012758, PubMed:26456828, PubMed:26898756, PubMed:27043296, PubMed:27180906, PubMed:30374165, PubMed:33067423). Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing (By similarity). Involved in DNA repair by promoting double-strand break (DSB) repair: acts as a DSB sensor by recognizing and binding DSB sites, leading to (1) recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of histone H3K9ac and H3K56ac (PubMed:23911928, PubMed:31995034, PubMed:32538779). SIRT6 participation to DSB repair is probably involved in extension of life span (By similarity). Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53 (PubMed:29474172, PubMed:32789493). Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence (PubMed:27043296). Involved in telomere maintenance by catalyzing deacetylation of histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage (PubMed:18337721, PubMed:19625767, PubMed:21847107). Required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac (PubMed:25915124, PubMed:29555651). Plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism (PubMed:24012758, PubMed:26787900). Inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, thereby controlling the expression of multiple glycolytic genes (By similarity). Has tumor suppressor activity by repressing glycolysis, thereby inhibiting the Warburg effect (PubMed:23217706). Also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2) (PubMed:26787900). Acts as a negative regulator of gluconeogenesis by mediating deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5 (PubMed:23142079, PubMed:25009184). Promotes beta-oxidation of fatty acids during fasting by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA (By similarity). Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1 (By similarity). Also acts as a regulator of circadian rhythms, both by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by catalyzing deacetylation of PER2 (By similarity). The defatty-acylase activity is specifically involved in regulation of protein secretion (PubMed:23552949, PubMed:24052263, PubMed:27322069, PubMed:28406396). Has high activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as RRAS2 and TNF, thereby regulating their secretion (PubMed:23552949, PubMed:28406396). Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170 (PubMed:21680843, PubMed:22753495, PubMed:27322069, PubMed:27568560). Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription (PubMed:21680843, PubMed:22753495, PubMed:27568560).
Post-translational modifications
Acetylated at Lys-33 (PubMed:32538779). Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites (PubMed:32538779).
Phosphorylation at Ser-10 by MAPK8/JNK1 in response to oxidative stress stimulates the mono-ADP-ribosyltransferase activity on PARP1, leading to PARP1 recruitment to double-strand breaks (DSBs).
Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its degradation by the proteasome. Deubiquitinated by USP10, also preventing its degradation by the proteasome (PubMed:37023208).
Sumoylated, leading to specifically decrease ability to deacetylate histone H3 at 'Lys-56' (H3K56ac).
Sequence Similarities
Belongs to the sirtuin family. Class IV subfamily.
Cellular localization
- Nucleus
- Chromosome
- Chromosome
- Telomere
- Endoplasmic reticulum
- Predominantly nuclear (PubMed:18337721). Associated with pericentric heterochromatin and telomeric heterochromatin regions (PubMed:18337721, PubMed:27043296). Localizes to DNA damage sites: directly recognizes and binds double-strand breaks (DSBs) sites via a tunnel-like structure that has high affinity for DSBs (PubMed:21680843, PubMed:23911928, PubMed:27568560, PubMed:31995034, PubMed:32538779). A fraction localizes to the endoplasmic reticulum (PubMed:23552949).
Alternative names
SIR2L6, SIRT6, NAD-dependent protein deacylase sirtuin-6, NAD-dependent protein deacetylase sirtuin-6, Protein mono-ADP-ribosyltransferase sirtuin-6, Regulatory protein SIR2 homolog 6, SIR2-like protein 6, hSIRT6