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Information on EC 2.1.1.366 - [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferase and Organism(s) Homo sapiens and UniProt Accession Q15047
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2.1.1.366 [histone H3]-N6,N6-dimethyl-lysine9 N-methyltransferaseIUBMB Comments
The enzyme methylates only dimethylated lysine9 of histone H3 (H3K9), forming the trimethylated form. This modification influences the binding of chromatin-associated proteins. In general, the methylation of H3K9 leads to transcriptional repression of the affected target genes. The enzyme is highly upregulated in Huntington disease patients. cf. EC 2.1.1.367, [histone H3]-lysine9 N-methyltransferase, and EC 2.1.1.368, [histone H3]-lysine9 N-dimethyltransferase, and EC 2.1.1.355, [histone H3]-lysine9 N-trimethyltransferase.
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
kmt1e, erg-associated protein with set domain, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
KIAA0067
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KMT1E
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SETDB1
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PATHWAY SOURCE
PATHWAYS
KEGG
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:[histone H3]-N6,N6-dimethyl-L-lysine9 N6-methyltransferase
The enzyme methylates only dimethylated lysine9 of histone H3 (H3K9), forming the trimethylated form. This modification influences the binding of chromatin-associated proteins. In general, the methylation of H3K9 leads to transcriptional repression of the affected target genes. The enzyme is highly upregulated in Huntington disease patients. cf. EC 2.1.1.367, [histone H3]-lysine9 N-methyltransferase, and EC 2.1.1.368, [histone H3]-lysine9 N-dimethyltransferase, and EC 2.1.1.355, [histone H3]-lysine9 N-trimethyltransferase.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
S-adenosyl-L-methionine + a [histone H3]-N6,N6-dimethyl-L-lysine9
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine9
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-
-
?
S-adenosyl-L-methionine + [histone H3 peptide 1-15]-L-lysine9
S-adenosyl-L-homocysteine + [histone H3 peptide 1-15]-N6-methyl-L-lysine9
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-
-
?
S-adenosyl-L-methionine + [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9
S-adenosyl-L-homocysteine + [histone H3 peptide 1-15]-N6,N6,N6-trimethyl-L-lysine9
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-
-
?
S-adenosyl-L-methionine + [histone H3 peptide 1-15]-N6-methyl-L-lysine9
S-adenosyl-L-homocysteine + [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9
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-
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?
additional information
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H3K9 methylation by SETDB1 occurs in a distributive manner
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
S-adenosyl-L-methionine + a [histone H3]-N6,N6-dimethyl-L-lysine9
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine9
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?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATF7IP
SETDB1 partner protein. SETDB1 and the SETDB1:ATF7IP complex efficiently catalyze both monomethylation and dimethylation of H3K9 peptide substrates. The activity of the binary complex is 4fold lower than SETDB1 alone
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.52
S-adenosyl-L-methionine
substrate [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9, SETDB1:ATF7IP complex, pH 7.6, 23°C
0.66
S-adenosyl-L-methionine
substrate [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9, pH 7.6, 23°C
0.39
[histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9
SETDB1:ATF7IP complex, pH 7.6, 23°C
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.013
S-adenosyl-L-methionine
substrate [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9, SETDB1:ATF7IP complex, pH 7.6, 23°C
0.065
S-adenosyl-L-methionine
substrate [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9, pH 7.6, 23°C
0.005
[histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9
SETDB1:ATF7IP complex, pH 7.6, 23°C
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.026
S-adenosyl-L-methionine
substrate [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9, SETDB1:ATF7IP complex, pH 7.6, 23°C
0.098
S-adenosyl-L-methionine
substrate [histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9, pH 7.6, 23°C
0.013
[histone H3 peptide 1-15]-N6,N6-dimethyl-L-lysine9
SETDB1:ATF7IP complex, pH 7.6, 23°C
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
expression is observed mainly in the cytoplasm of various human cell lines
combined treatment with the nuclear export inhibitor leptomycin B and the proteasome inhibitor MG132 leads to the accumulation of SETDB1 in the nucleus
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
physiological function
ATFa-associated factor mAM stimulates ESET enzymatic activity by increasing the Vmax and decreasing the Km. mAM facilitates the ESET-dependent conversion of dimethyl H3-K9 to the trimethyl state both in vitro and in vivo. mAM enhances ESET-mediated transcriptional repression in a SAM-dependent manner, and this repression correlates with histone H3-K9 trimethylation at the promoter
physiological function
embryonic stem cells exhibit high expression of the ubiquitin-conjugating enzyme UBE2K. Loss of UBE2K upregulates the trimethyltransferase SETDB1, resulting in H3K9 trimethylation and repression of neurogenic genes during differentiation
physiological function
histone H3K9 methyltransferases G9a/KMT1C, GLP/KMT1D, SETDB1/KMT1E, and Suv39h1/KMT1A, coexist in the same megacomplex. In Suv39h or G9a null cells, the remaining histone H3K9 methyltransferases are destabilized at the protein level, indicating. The four enzymes are recruited to major satellite repeats, a known Suv39h1 genomic target, but also to multiple G9a target genes. The four H3K9 histone H3K9 methyltransferases display a functional cooperation in the regulation of known G9a target genes
physiological function
microRNA, miR-152-3p is involved in the regulation of SETDB1 protein levels and plays a positive regulatory role for SETDB1 expression. Inhibition of miR-152-3p results in a robust reduction in SETDB1 protein levels, though SETDB1 mRNA levels are unaffected. This is accompanied by a blockade of the biochemical pathway proceeding from H3K9me2 to H3K9me3. H3K9me2 accumulates in cells treated with an anti-miR that targets miR-152-3p. The action of a miR-152-3p mimic increases flux of the reaction leading to H3K9me3
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). SETB1_HUMAN
1291
0
143157
Swiss-Prot
other Location (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
expression of an inactivated form of SETDB1 in human pancreatic ductal adenocarcinoma cells with wild-type TP53 results in TP53-induced apoptosis
medicine
overexpression of SETDB1 contributes to melanoma tumorigenesis. SETDB1 is highly amplified in melanoma cells and in the patient tumors. Increased expression of SETDB1 correlates with SETDB1 amplification and is associated with a more aggressive phenotype in in vitro and in vivo studies. SETDB1 implements its effects via regulation of thrombospondin 1, and the SET-domain of SETDB1 is essential for the maintenance of its tumorigenic activity. Inhibition of SETDB1 reduces cell growth in melanomas resistant to targeted treatments
medicine
SETDB1 depletion effectively converts stem-like colorectal cancer cells into postmitotic cells and restores normal morphology in patient-derived colorectal cancer organoids. SETDB1 depletion recapitulates global gene expression profiles of normal differentiated cells by restoring the transcriptional activity of core transcription factors such as CDX2, ELF3, HNF4G, PPARG, and VDR, on their target genes
medicine
SETDB1 expression is highly amplified in colorectal cancer. SETDB1 downregulation in SW480 and HCT116 cells reduces cell proliferation, migration, invasion, and increased colorectal cancer cells apoptosis. SETDB1 overexpression promotes colorectal cancer cells proliferation, migration, and invasion. High expression of SETDB1 is associated with a more aggressive phenotype in vitro. Cell cycle is arrested in G1 phase after SETDB1 silencing. Depletion of SETDB1 in vivo suppresses colorectal cancer cells proliferation. p21 is the target of SETDB1. After transfection with siSETDB1, expression of p21 s distinctly increased. Expression of p21 is significantly decreased after overexpression of SETDB1. SETDB1 can bind to the promoter of p21 and regulate its H3K9me3 enrichment level. Silencing of SETDB1 inhibits colorectal cancer tumorigenesis in vivo
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wang, H.; An, W.; Cao, R.; Xia, L.; Erdjument-Bromage, H.; Chatton, B.; Tempst, P.; Roeder, R.G.; Zhang, L.
mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression
Mol. Cell
12
475-487
2003
Homo sapiens (Q15047)
Tachibana, K.; Gotoh, E.; Kawamata, N.; Ishimoto, K.; Uchihara, Y.; Iwanari, H.; Sugiyama, A.; Kawamura, T.; Mochizuki, Y.; Tanaka, T.; Sakai, J.; Hamakubo, T.; Kodama, T.; Doi, T.
Analysis of the subcellular localization of the human histone methyltransferase SETDB1
Biochem. Biophys. Res. Commun.
465
725-731
2015
Homo sapiens (Q15047)
Basavapathruni, A.; Gureasko, J.; Porter Scott, M.; Hermans, W.; Godbole, A.; Leland, P.A.; Boriack-Sjodin, P.A.; Wigle, T.J.; Copeland, R.A.; Riera, T.V.
Characterization of the enzymatic activity of SETDB1 and its 1 1 complex with ATF7IP
Biochemistry
55
1645-1651
2016
Homo sapiens (Q15047)
Cao, N.; Yu, Y.; Zhu, H.; Chen, M.; Chen, P.; Zhuo, M.; Mao, Y.; Li, L.; Zhao, Q.; Wu, M.; Ye, M.
SETDB1 promotes the progression of colorectal cancer via epigenetically silencing p21 expression
Cell Death Dis.
11
351
2020
Homo sapiens (Q15047)
Fatima, A.; Irmak, D.; Noormohammadi, A.; Rinschen, M.M.; Das, A.; Leidecker, O.; Schindler, C.; Sanchez-Gaya, V.; Wagle, P.; Pokrzywa, W.; Hoppe, T.; Rada-Iglesias, A.; Vilchez, D.
The ubiquitin-conjugating enzyme UBE2K determines neurogenic potential through histone H3 in human embryonic stem cells
Commun. Biol.
3
262
2020
Homo sapiens (Q15047)
Singh, S.K.; Bahal, R.; Rasmussen, T.P.
Evidence that miR-152-3p is a positive regulator of SETDB1-mediated H3K9 histone methylation and serves as a toggle between histone and DNA methylation
Exp. Cell Res.
395
112216
2020
Homo sapiens (Q15047)
Ogawa, S.; Fukuda, A.; Matsumoto, Y.; Hanyu, Y.; Sono, M.; Fukunaga, Y.; Masuda, T.; Araki, O.; Nagao, M.; Yoshikawa, T.; Goto, N.; Hiramatsu, Y.; Tsuda, M.; Maruno, T.; Nakanishi, Y.; Hussein, M.S.; Tsuruyama, T.; Takaori, K.; Uemoto, S.; Seno, H.
SETDB1 inhibits p53-mediated apoptosis and is required for formation of pancreatic ductal adenocarcinomas in mice
Gastroenterology
159
682-696.e13
2020
Homo sapiens (Q15047), Mus musculus (O88974)
Orouji, E.; Federico, A.; Larribere, L.; Novak, D.; Lipka, D.B.; Assenov, Y.; Sachindra, S.; Hueser, L.; Granados, K.; Gebhardt, C.; Plass, C.; Umansky, V.; Utikal, J.
Histone methyltransferase SETDB1 contributes to melanoma tumorigenesis and serves as a new potential therapeutic target
Int. J. Cancer
145
3462-3477
2019
Mus musculus (O88974), Homo sapiens (Q15047)
Lee, S.; Lee, C.; Hwang, C.Y.; Kim, D.; Han, Y.; Hong, S.N.; Kim, S.H.; Cho, K.H.
Network inference analysis identifies SETDB1 as a key regulator for reverting colorectal cancer cells into differentiated normal-like cells
Mol. Cancer Res.
18
118-129
2020
Homo sapiens (Q15047)
Fritsch, L.; Robin, P.; Mathieu, J.R.; Souidi, M.; Hinaux, H.; Rougeulle, C.; Harel-Bellan, A.; Ameyar-Zazoua, M.; Ait-Si-Ali, S.
A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex
Mol. Cell
37
46-56
2010
Homo sapiens (Q15047)
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