SIRT6
entrez
51548
canonical
uniprot
Q8N6T7
canonical
ensembl
ENSG00000077463
resolver
ensp
ENSP00000305310
resolver
ensp
ENSP00000337332
resolver
ensp
ENSP00000469001
resolver
ensp
ENSP00000470215
resolver
ensp
ENSP00000472023
resolver
ensp
ENSP00000640188
resolver
ensp
ENSP00000676673
resolver
enst
ENST00000594279
resolver
enst
ENST00000601488
resolver
genesymbol
SIRT6
resolver
genesymbol_syn
SIR2L6
resolver
hgnc
HGNC:14934
resolver
uniprot
B2RCD0
resolver
uniprot
B4DDV3
resolver
uniprot
M0QXA0
resolver
uniprot
M0R1N9
resolver
uniprot
O75291
resolver
uniprot
Q6IAF5
resolver
uniprot
Q6PK99
resolver
uniprot
Q8NCD2
resolver
uniprot
Q9BSI5
resolver
uniprot
Q9BWP3
resolver
uniprot
Q9NRC7
resolver
uniprot
Q9UQD1
resolver
uniprot_entry
B4DDV3_HUMAN
resolver
uniprot_entry
M0QXA0_HUMAN
resolver
uniprot_entry
M0R1N9_HUMAN
resolver
uniprot_entry
SIR6_HUMAN
resolver
uniprot_sec
B2RCD0
resolver
uniprot_sec
O75291
resolver
uniprot_sec
Q6IAF5
resolver
uniprot_sec
Q6PK99
resolver
uniprot_sec
Q8NCD2
resolver
uniprot_sec
Q9BSI5
resolver
uniprot_sec
Q9BWP3
resolver
uniprot_sec
Q9NRC7
resolver
uniprot_sec
Q9UQD1
resolver
activity_regulation
ACTIVITY REGULATION: Compared to the defatty-acylase activity, the protein deacetylase activity is weak in vitro, and requires activation (PubMed:21362626, PubMed:23552949, PubMed:23892288, PubMed:24052263). The histone deacetylase activity is strongly activated upon binding to nucleosomes and chromatin in vivo (PubMed:23892288, PubMed:27043296, PubMed:33067423). Two molecules of SIRT6 associate with the acidic patch of one nucleosome, while the C-terminal disordered region of SIRT6 associates with nucleosomal DNA, leading to efficient histone deacetylation (PubMed:33067423). The protein-lysine deacetylase activity is also activated by long-chain free fatty-acids (PubMed:24052263). The histone deacetylase activity is specifically repressed by long non-coding RNA lncPRESS1, which binds to SIRT6 and prevents chromatin-binding, thereby promoting stem cell pluripotency (PubMed:27912097). Due to its essential role as tumor suppressor and involvement in DNA repair and life span, extensive research is made for the identification of small compound regulators of SIRT6 (PubMed:27990725, PubMed:30374165, PubMed:30395713, PubMed:31844103, PubMed:33214841, PubMed:33649599, PubMed:33649600). Nitro-fatty acids (nitro-oleic acid and nitro-conjugated linoleic acid) strongly stimulate the protein-lysine deacetylase activity by forming a covalent Michael adduct formation with Cys-18 (PubMed:33122195). Activated by UBCS039 (4-(pyridin-3-yl)-4,5- dihydropyrrolo[1,2-a]quinoxaline) (PubMed:27990725). Inhibited by non-selective hydroxamate trichostatin A inhibitor (PubMed:30395713). Deacetylase activity is activated by fluvastatin and quercetin-based compounds (PubMed:31844103, PubMed:33214841). The protein-lysine deacetylase activity, but not the defatty-acylase activity, is specifically activated by MDL-800 and MDL-801 activators in vivo, enhancing the histone deacetylase and tumor suppressor activities (PubMed:30374165, PubMed:33649599, PubMed:33649600). MDL-800 and MDL-801 selectively activate SIRT6 and not other members of the sirtuin family (PubMed:30374165). The binding-mode of MDL-801 is however subject to discussion (PubMed:30374165, PubMed:33649599, PubMed:33649600). {ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27912097, ECO:0000269|PubMed:27990725, ECO:0000269|PubMed:30374165, ECO:0000269|PubMed:30395713, ECO:0000269|PubMed:31844103, ECO:0000269|PubMed:33067423, ECO:0000269|PubMed:33122195, ECO:0000269|PubMed:33214841, ECO:0000269|PubMed:33649599, ECO:0000269|PubMed:33649600}.
uniprot
proteins
amino_acid_sequence
MSVNYAAGLSPYADKGKCGLPEIFDPPEELERKVWELARLVWQSSSVVFHTGAGISTASGIPDFRGPHGVWTMEERGLAPKFDTTFESARPTQTHMALVQLERVGLLRFLVSQNVDGLHVRSGFPRDKLAELHGNMFVEECAKCKTQYVRDTVVGTMGLKATGRLCTVAKARGLRACRGELRDTILDWEDSLPDRDLALADEASRNADLSITLGTSLQIRPSGNLPLATKRRGGRLVIVNLQPTKHDRHADLRIHGYVDEVMTRLMKHLGLEIPAWDGPRVLERALPPLPRPPTPKLEPKEESPTRINGSIPAGPKQEPCAQHNGSEPASPKRERPTSPAPHRPPKRVKAKAVPS
uniprot
proteins
ec_number
2.3.1.-
uniprot
proteins
ec_number
2.3.1.286
uniprot
proteins
ec_number
2.4.2.-
uniprot
proteins
function
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). {ECO:0000250|UniProtKB:P59941, ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:19135889, ECO:0000269|PubMed:19625767, ECO:0000269|PubMed:21362626, ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:21847107, ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:23142079, ECO:0000269|PubMed:23217706, ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:23653361, ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:24012758, ECO:0000269|PubMed:24052263, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:25915124, ECO:0000269|PubMed:26456828, ECO:0000269|PubMed:26787900, ECO:0000269|PubMed:26898756, ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27180906, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27568560, ECO:0000269|PubMed:28406396, ECO:0000269|PubMed:29474172, ECO:0000269|PubMed:29555651, ECO:0000269|PubMed:30374165, ECO:0000269|PubMed:31995034, ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32789493, ECO:0000269|PubMed:33067423}.
uniprot
proteins
mass_dalton
39119
uniprot
proteins
mutagenesis
MUTAGEN 10; /note="S->A: Abolishes ability to promote DNA repair and recruit PARP1 to double-strand breaks (DSBs)."; /evidence="ECO:0000269|PubMed:27568560"; MUTAGEN 10; /note="S->E: Mimics phosphorylation; increased ability to promote DNA repair and recruit PARP1 to double-strand breaks (DSBs)."; /evidence="ECO:0000269|PubMed:27568560"; MUTAGEN 13; /note="A->W: Increased protein-lysine demyristoylase activity."; /evidence="ECO:0000269|PubMed:31995034"; MUTAGEN 15; /note="K->R: Does not affect acetylation level."; /evidence="ECO:0000269|PubMed:32538779"; MUTAGEN 17; /note="K->R: Does not affect acetylation level."; /evidence="ECO:0000269|PubMed:32538779"; MUTAGEN 33; /note="K->Q: Mimics acetylation, leading to impaired ability to recognize and bind double-strand breaks (DSBs) sites."; /evidence="ECO:0000269|PubMed:32538779"; MUTAGEN 33; /note="K->R: Decreased acetylation level."; /evidence="ECO:0000269|PubMed:32538779"; MUTAGEN 45; /note="S->A: In AAA mutant; strongly decreased nucleosome-binding; when associated with 206-A--A-208."; /evidence="ECO:0000269|PubMed:33067423"; MUTAGEN 56; /note="S->Y: Abolished NAD-dependent protein deacetylase, defatty-acylase and mono-ADP-ribosyltransferase activities."; /evidence="ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:32789493"; MUTAGEN 60; /note="G->A: Does not affect the NAD-dependent protein defatty-acylase activity. Abolished NAD-dependent protein deacetylase and mono-ADP-ribosyltransferase activities."; /evidence="ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:28406396"; MUTAGEN 65; /note="R->A: Does not affect the mono-ADP-ribosyltransferase activity. Abolished NAD-dependent protein deacetylase and defatty-acylase activities."; /evidence="ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:22753495, ECO:0000269|PubMed:27322069"; MUTAGEN 82; /note="F->A,E: Reduced MDL-800 and MDL-801 compounds-binding."; /evidence="ECO:0000269|PubMed:30374165"; MUTAGEN 86; /note="F->E: Strongly reduced MDL-800 and MDL-801 compounds-binding."; /evidence="ECO:0000269|PubMed:30374165"; MUTAGEN 86; /note="F->Q: Slightly reduced MDL-800 and MDL-801 compounds-binding."; /evidence="ECO:0000269|PubMed:30374165"; MUTAGEN 133; /note="H->Y: Abolished NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase activities. Impaired ability to recognize and bind double-strand breaks (DSBs) sites."; /evidence="ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:23142079, ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:23892288, ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:26787900, ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:28406396, ECO:0000269|PubMed:29474172, ECO:0000269|PubMed:31995034, ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32789493"; MUTAGEN 170; /note="K->R: Decreased ubiquitination."; /evidence="ECO:0000269|PubMed:24043303"; MUTAGEN 206..208; /note="Missing: In AAA mutant; strongly decreased nucleosome-binding; when associated with A-45."; /evidence="ECO:0000269|PubMed:33067423"; MUTAGEN 294; /note="T->A: Does not affect ability to promote DNA repair."; /evidence="ECO:0000269|PubMed:27568560"; MUTAGEN 296..300; /note="KLEPK->RLEPR: In 4KR mutant; abolished sumoylation, leading to increased H3K56ac; when associated with R-316 and R-332."; /evidence="ECO:0000269|PubMed:26898756"; MUTAGEN 303; /note="S->A: Does not affect ability to promote DNA repair."; /evidence="ECO:0000269|PubMed:27568560"; MUTAGEN 316; /note="K->R: In 4KR mutant; abolished sumoylation, leading to increased H3K56ac; when associated with 296-R--R-300 and R-332."; /evidence="ECO:0000269|PubMed:26898756"; MUTAGEN 330; /note="S->A: Does not affect ability to promote DNA repair."; /evidence="ECO:0000269|PubMed:27568560"; MUTAGEN 332; /note="K->R: In 4KR mutant; abolished sumoylation, leading to increased H3K56ac; when associated with 296-R--R-300 and R-316."; /evidence="ECO:0000269|PubMed:26898756"; MUTAGEN 338; /note="S->A: Does not affect ability to promote DNA repair."; /evidence="ECO:0000269|PubMed:27568560
uniprot
proteins
post_translational_modification
PTM: Acetylated at Lys-33 (PubMed:32538779). Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites (PubMed:32538779). {ECO:0000269|PubMed:32538779}.; PTM: 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). {ECO:0000269|PubMed:27568560}.; PTM: 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). {ECO:0000269|PubMed:24043303, ECO:0000269|PubMed:37023208}.; PTM: Sumoylated, leading to specifically decrease ability to deacetylate histone H3 at 'Lys-56' (H3K56ac). {ECO:0000269|PubMed:26898756}.
uniprot
proteins
protein_family
Class IV subfamily
uniprot
proteins
protein_family
Sirtuin family
uniprot
proteins
pubmed
10873683
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15057824
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16079181
uniprot
proteins
pubmed
18337721
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
19135889
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19625767
uniprot
proteins
pubmed
20829486
uniprot
proteins
pubmed
21362626
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
21680843
uniprot
proteins
pubmed
21847107
uniprot
proteins
pubmed
22753495
uniprot
proteins
pubmed
23142079
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23217706
uniprot
proteins
pubmed
23552949
uniprot
proteins
pubmed
23653361
uniprot
proteins
pubmed
23892288
uniprot
proteins
pubmed
23911928
uniprot
proteins
pubmed
24012758
uniprot
proteins
pubmed
24043303
uniprot
proteins
pubmed
24052263
uniprot
proteins
pubmed
24275569
uniprot
proteins
pubmed
25009184
uniprot
proteins
pubmed
25541994
uniprot
proteins
pubmed
25915124
uniprot
proteins
pubmed
26456828
uniprot
proteins
pubmed
26748705
uniprot
proteins
pubmed
26787900
uniprot
proteins
pubmed
26898756
uniprot
proteins
pubmed
27043296
uniprot
proteins
pubmed
27180906
uniprot
proteins
pubmed
27322069
uniprot
proteins
pubmed
27568560
uniprot
proteins
pubmed
27912097
uniprot
proteins
pubmed
27990725
uniprot
proteins
pubmed
28406396
uniprot
proteins
pubmed
29474172
uniprot
proteins
pubmed
29555651
uniprot
proteins
pubmed
30374165
uniprot
proteins
pubmed
30395713
uniprot
proteins
pubmed
30975768
uniprot
proteins
pubmed
31844103
uniprot
proteins
pubmed
31995034
uniprot
proteins
pubmed
32538779
uniprot
proteins
pubmed
32789493
uniprot
proteins
pubmed
33067423
uniprot
proteins
pubmed
33122195
uniprot
proteins
pubmed
33214841
uniprot
proteins
pubmed
33649599
uniprot
proteins
pubmed
33649600
uniprot
proteins
pubmed
37023208
uniprot
proteins
sequence_length
355
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16079181, ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:19135889, ECO:0000269|PubMed:26456828, ECO:0000269|PubMed:26898756, ECO:0000269|PubMed:29555651}. Chromosome {ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:26456828, ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27568560, ECO:0000269|PubMed:27912097, ECO:0000269|PubMed:31995034, ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32789493}. Chromosome, telomere {ECO:0000269|PubMed:18337721}. Endoplasmic reticulum {ECO:0000269|PubMed:23552949}. Note=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). {ECO:0000269|PubMed:18337721, ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:23552949, ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:27043296, ECO:0000269|PubMed:27568560, ECO:0000269|PubMed:31995034, ECO:0000269|PubMed:32538779}.
uniprot
proteins