Sirt6
entrez
50721
canonical
uniprot
P59941
canonical
ensembl
ENSMUSG00000034748
resolver
ensp
ENSMUSP00000048971
resolver
ensp
ENSMUSP00000113953
resolver
ensp
ENSMUSP00000244485
resolver
enst
ENSMUST00000042923
resolver
enst
ENSMUST00000119324
resolver
genesymbol
Sirt6
resolver
genesymbol_syn
Sir2l6
resolver
uniprot
F7CRR4
resolver
uniprot
Q3UKP1
resolver
uniprot_entry
F7CRR4_MOUSE
resolver
uniprot_entry
Q3UKP1_MOUSE
resolver
uniprot_entry
SIR6_MOUSE
resolver
activity_regulation
ACTIVITY REGULATION: Compared to the defatty-acylase activity, the protein deacetylase activity is weak in vitro, and requires activation (By similarity). The histone deacetylase activity is strongly activated upon binding to nucleosomes and chromatin in vivo (By similarity). 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 (By similarity). The protein-lysine deacetylase activity is also activated by long-chain free fatty-acids (By similarity). {ECO:0000250|UniProtKB:Q8N6T7}.
uniprot
proteins
amino_acid_sequence
MSVNYAAGLSPYADKGKCGLPEIFDPPEELERKVWELARLMWQSSSVVFHTGAGISTASGIPDFRGPHGVWTMEERGLAPKFDTTFENARPSKTHMALVQLERMGFLSFLVSQNVDGLHVRSGFPRDKLAELHGNMFVEECPKCKTQYVRDTVVGTMGLKATGRLCTVAKTRGLRACRGELRDTILDWEDSLPDRDLMLADEASRTADLSVTLGTSLQIRPSGNLPLATKRRGGRLVIVNLQPTKHDRQADLRIHGYVDEVMCRLMKHLGLEIPAWDGPCVLDKALPPLPRPVALKAEPPVHLNGAVHVSYKSKPNSPILHRPPKRVKTEAAPS
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:16439206, PubMed:19135889, PubMed:19220062, PubMed:19597350, PubMed:20141841, PubMed:23217706, PubMed:23911928, PubMed:27180906, PubMed:29599436). Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context (By similarity). 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:19135889, PubMed:19597350, PubMed:20816089, PubMed:21098266, PubMed:25915124, PubMed:28871079, PubMed:31002797, PubMed:31399344). Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing (PubMed:31399344). 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:32538779). SIRT6 participation to DSB repair is probably involved in extension of life span (PubMed:22367546, PubMed:31002797). Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53 (By similarity). Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence (By similarity). 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:29599436). 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:20141841, PubMed:20816089, PubMed:20847051, PubMed:21098266, PubMed:23974119, PubMed:27457971, PubMed:28250020, PubMed:28355567, PubMed:34050173). 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 (PubMed:20141841). 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) (By similarity). 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 (PubMed:31851938). Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1 (PubMed:28723567, PubMed:31442424). 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 (PubMed:25083875, PubMed:30782483). The defatty-acylase activity is specifically involved in regulation of protein secretion (PubMed:19151729, PubMed:27322069). 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 (By similarity). Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170 (PubMed:15795229, PubMed:21680843, PubMed:25247314, PubMed:31216030). Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription (PubMed:21680843, PubMed:25247314, PubMed:30853213, PubMed:31216030, PubMed:32584788). {ECO:0000250|UniProtKB:Q8N6T7, ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:16439206, ECO:0000269|PubMed:19135889, ECO:0000269|PubMed:19151729, ECO:0000269|PubMed:19220062, ECO:0000269|PubMed:19597350, ECO:0000269|PubMed:20141841, ECO:0000269|PubMed:20816089, ECO:0000269|PubMed:20847051, ECO:0000269|PubMed:21098266, ECO:0000269|PubMed:21680843, ECO:0000269|PubMed:22367546, ECO:0000269|PubMed:23142079, ECO:0000269|PubMed:23217706, ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:23974119, ECO:0000269|PubMed:25009184, ECO:0000269|PubMed:25083875, ECO:0000269|PubMed:25247314, ECO:0000269|PubMed:25915124, ECO:0000269|PubMed:27180906, ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27457971, ECO:0000269|PubMed:28250020, ECO:0000269|PubMed:28355567, ECO:0000269|PubMed:28723567, ECO:0000269|PubMed:28871079, ECO:0000269|PubMed:29555651, ECO:0000269|PubMed:29599436, ECO:0000269|PubMed:30782483, ECO:0000269|PubMed:30853213, ECO:0000269|PubMed:31002797, ECO:0000269|PubMed:31216030, ECO:0000269|PubMed:31399344, ECO:0000269|PubMed:31442424, ECO:0000269|PubMed:31851938, ECO:0000269|PubMed:32538779, ECO:0000269|PubMed:32584788, ECO:0000269|PubMed:34050173}.
uniprot
proteins
mass_dalton
36920
uniprot
proteins
mutagenesis
MUTAGEN 56; /note="S->Y,A: Abolished NAD-dependent protein deacetylase, defatty-acylase and mono-ADP-ribosyltransferase activities."; /evidence="ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:25247314"; 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:25247314, ECO:0000269|PubMed:31216030"; MUTAGEN 63; /note="D->H: Embryonic lethality in knockin mice; mice fail to form embryonic bodies and retain pluripotent gene expression, leading to impaired embryonic stem cell differentiation. Defects are caused by a failure to deacetylate histone H3 at 'Lys-9' (H3K9)."; /evidence="ECO:0000269|PubMed:29555651"; 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:25247314, ECO:0000269|PubMed:31216030"; MUTAGEN 133; /note="H->Y: Abolished NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase activities."; /evidence="ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:19597350, ECO:0000269|PubMed:27457971, ECO:0000269|PubMed:29599436, ECO:0000269|PubMed:31216030"; MUTAGEN 235; /note="R->K: Increased histone deacetylase activity, ability to promote double-strand break (DSB) repair, leading to increased life span; when associated with H-249 and 260-D--Q-264."; /evidence="ECO:0000269|PubMed:31002797"; MUTAGEN 249; /note="Q->H: Increased histone deacetylase activity, ability to promote double-strand break (DSB) repair, leading to increased life span; when associated with K-235 and 260-D--Q-264."; /evidence="ECO:0000269|PubMed:31002797"; MUTAGEN 260..264; /note="EVMCR->DVMTQ: Increased histone deacetylase activity, ability to promote double-strand break (DSB) repair, leading to increased life span; when associated with K-235 and H-249."; /evidence="ECO:0000269|PubMed:31002797
uniprot
proteins
post_translational_modification
PTM: Acetylated at Lys-33 (By similarity). Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites (By similarity). {ECO:0000250|UniProtKB:Q8N6T7}.; 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:0000250|UniProtKB:Q8N6T7}.; PTM: Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its degradation by the proteasome. {ECO:0000250|UniProtKB:Q8N6T7}.; PTM: Sumoylated, leading to specifically decrease ability to deacetylate histone H3 at 'Lys-56' (H3K56ac). {ECO:0000250|UniProtKB:Q8N6T7}.
uniprot
proteins
protein_family
Class IV subfamily
uniprot
proteins
protein_family
Sirtuin family
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15795229
uniprot
proteins
pubmed
16439206
uniprot
proteins
pubmed
19135889
uniprot
proteins
pubmed
19151729
uniprot
proteins
pubmed
19220062
uniprot
proteins
pubmed
19597350
uniprot
proteins
pubmed
20141841
uniprot
proteins
pubmed
20816089
uniprot
proteins
pubmed
20847051
uniprot
proteins
pubmed
21098266
uniprot
proteins
pubmed
21680843
uniprot
proteins
pubmed
22367546
uniprot
proteins
pubmed
23142079
uniprot
proteins
pubmed
23217706
uniprot
proteins
pubmed
23552949
uniprot
proteins
pubmed
23911928
uniprot
proteins
pubmed
23974119
uniprot
proteins
pubmed
25009184
uniprot
proteins
pubmed
25083875
uniprot
proteins
pubmed
25247314
uniprot
proteins
pubmed
25915124
uniprot
proteins
pubmed
27180906
uniprot
proteins
pubmed
27322069
uniprot
proteins
pubmed
27457971
uniprot
proteins
pubmed
28250020
uniprot
proteins
pubmed
28355567
uniprot
proteins
pubmed
28448551
uniprot
proteins
pubmed
28723567
uniprot
proteins
pubmed
28871079
uniprot
proteins
pubmed
29474172
uniprot
proteins
pubmed
29555651
uniprot
proteins
pubmed
29599436
uniprot
proteins
pubmed
30530497
uniprot
proteins
pubmed
30782483
uniprot
proteins
pubmed
30853213
uniprot
proteins
pubmed
31002797
uniprot
proteins
pubmed
31216030
uniprot
proteins
pubmed
31399344
uniprot
proteins
pubmed
31442424
uniprot
proteins
pubmed
31851938
uniprot
proteins
pubmed
32538779
uniprot
proteins
pubmed
32584788
uniprot
proteins
pubmed
34050173
uniprot
proteins
sequence_length
334
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:16439206}. Chromosome {ECO:0000250|UniProtKB:Q8N6T7}. Chromosome, telomere {ECO:0000250|UniProtKB:Q8N6T7}. Endoplasmic reticulum {ECO:0000269|PubMed:23552949}. Note=Predominantly nuclear (By similarity). Associated with pericentric heterochromatin and telomeric heterochromatin regions (By similarity). 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 (By similarity). A fraction localizes to the endoplasmic reticulum (PubMed:23552949). {ECO:0000250|UniProtKB:Q8N6T7, ECO:0000269|PubMed:23552949}.
uniprot
proteins