Any feedback?
Information on EC 2.1.1.359 - [histone H3]-lysine36 N-trimethyltransferase and Organism(s) Homo sapiens and UniProt Accession O96028
for references in articles please use BRENDA:EC2.1.1.359Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
2.1.1.359 [histone H3]-lysine36 N-trimethyltransferaseIUBMB Comments
The enzyme, characterized from yeast and mammals, catalyses the successive methylation of lysine36 of histone H3 (H3K36), forming the trimethylated form. These modifications influence the binding of chromatin-associated proteins. The enzyme couples the methylation reactions with transcriptional elongation through an interaction with the large subunit of RNA polymerase II. cf. EC 2.1.1.357, [histone H3]-lysine36 N-dimethyltransferase.
Specify your search results
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
hide(Overall reactions are displayed. Show all >>)
Synonyms
met-1, histone lysine methyltransferases, set domain containing 2, wolf-hirschhorn syndrome candidate 1, sdg725, histone h3k36 methyltransferase, h3k36 trimethyltransferase, set domain containing protein 2, kmt3a, h3k36me3 methyltransferase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
histone H3 lysine 36 methyltransferase
HYPB
SET2
SETD2
SET2
-
-
-
-
SETD2
-
PATHWAY SOURCE
PATHWAYS
KEGG
SYSTEMATIC NAME
IUBMB Comments
S-adenosyl-L-methionine:[histone H3]-L-lysine36 N6-trimethyltransferase
The enzyme, characterized from yeast and mammals, catalyses the successive methylation of lysine36 of histone H3 (H3K36), forming the trimethylated form. These modifications influence the binding of chromatin-associated proteins. The enzyme couples the methylation reactions with transcriptional elongation through an interaction with the large subunit of RNA polymerase II. cf. EC 2.1.1.357, [histone H3]-lysine36 N-dimethyltransferase.
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
2 S-adenosyl-L-methionine + [histone H4]-L-lysine44
2 S-adenosyl-L-homocysteine + [histone H4]-N6,N6-dimethyl-L-lysine44
histone H4 lysine-44 is the primary target of NSD2 in the case of octamer substrates, irrespective of the histones being native or recombinant
-
-
?
S-adenosyl-L-methionine + histone H3(K36)
?
NSD2 shows specific targeting of histone H3 lysine-36, DNA acts as an allosteric effector of NSD2 such that H3K36 becomes the preferred target
-
-
?
3 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
3 S-adenosyl-L-methionine + [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + [histone H3]-N6,N6,N6-trimethyl-L-lysine36
overall reaction
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6,N6-dimethyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + chicken nucleosome
S-adenosyl-L-homocysteine + chicken nucleosome N6-methyl-L-lysine
-
-
-
?
S-adenosyl-L-methionine + histone H3(K36)
S-adenosyl-L-homocysteine + histone H3(K36) N6-methyl-L-lysine
-
-
-
?
S-adenosyl-L-methionine + histone H3(peptide 21-44)
S-adenosyl-L-homocysteine + histone H3(peptide21-44) N6-methyl-L-lysine
-
-
-
?
S-adenosyl-L-methionine + recombinant nucleosome
S-adenosyl-L-homocysteine + recombinant nucleosome N6-methyl-L-lysine
-
-
-
?
S-adenosyl-L-methionine + [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + [histone H3]-N6,N6-dimethyl-L-lysine36
S-adenosyl-L-homocysteine + [histone H3]-N6,N6,N6-trimethyl-L-lysine36
highest activity
-
-
?
S-adenosyl-L-methionine + [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
3 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
overall reaction
-
-
?
3 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
overall reaction
-
-
?
additional information
?
-
-
SETD2 downregulates human ortholog of murine double min 2 protein expression by targeting its P2 promoter and then enhances p53 protein stability, enhances the transcriptional activity of p53, and regulates expression of select p53 target genes
-
-
?
additional information
?
-
enzyme mono- and dimethylates H3K36 and is inactive with H3K4 as substrate. Nucleosome containing histone H3 mutant K36A is not a substrate. Isoform SETD2 is able to trimethylate H3K36 in vitro
-
-
?
additional information
?
-
no activity with unmethylated/methylated [histone H3]-L-lysine27 and [histone H3]-L-lysine20 as well as trimethylated [histone H3]-L-lysine4 and [histone H3]-L-lysine36 peptides
-
-
?
additional information
?
-
the enzyme also efficiently trimethylates [histone H3]-L-lysine4
-
-
?
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
3 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
3 S-adenosyl-L-methionine + [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + [histone H3]-N6,N6,N6-trimethyl-L-lysine36
overall reaction
-
-
?
S-adenosyl-L-methionine + a [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6,N6-dimethyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + a [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + a [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + [histone H3]-L-lysine36
S-adenosyl-L-homocysteine + [histone H3]-N6-methyl-L-lysine36
-
-
-
?
S-adenosyl-L-methionine + [histone H3]-N6,N6-dimethyl-L-lysine36
S-adenosyl-L-homocysteine + [histone H3]-N6,N6,N6-trimethyl-L-lysine36
highest activity
-
-
?
S-adenosyl-L-methionine + [histone H3]-N6-methyl-L-lysine36
S-adenosyl-L-homocysteine + [histone H3]-N6,N6-dimethyl-L-lysine36
-
-
-
?
3 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
overall reaction
-
-
?
3 S-adenosyl-L-methionine + a [histone H3]-L-lysine36
3 S-adenosyl-L-homocysteine + a [histone H3]-N6,N6,N6-trimethyl-L-lysine36
overall reaction
-
-
?
additional information
?
-
no activity with unmethylated/methylated [histone H3]-L-lysine27 and [histone H3]-L-lysine20 as well as trimethylated [histone H3]-L-lysine4 and [histone H3]-L-lysine36 peptides
-
-
?
additional information
?
-
the enzyme also efficiently trimethylates [histone H3]-L-lysine4
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0033
S-adenosyl-L-methionine
cosubstrate recombinant nucleosome, pH 9.0, 23°C
0.004
S-adenosyl-L-methionine
cosubstrate chicken nucleosome, pH 9.0, 23°C
0.0055
S-adenosyl-L-methionine
cosubstrate histone H3(peptide 21-44), pH 9.0, 23°C
0.062
S-adenosyl-L-methionine
with [histone H3]-N6,N6-dimethyl-L-lysine36 as cosubstrate, at pH 8.5 and 23°C
0.087
S-adenosyl-L-methionine
with [histone H3]-L-lysine36 as cosubstrate, at pH 8.5 and 23°C
0.13
S-adenosyl-L-methionine
with [histone H3]-N6-methyl-L-lysine36 as cosubstrate, at pH 8.5 and 23°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
ASH1 knockdown causes reduced expression of Hox genes. Knockdown of ASH1 in K-562 cells in vitro causes increased expression of epsilon-globin gene and reduced expression of myelomonocytic markers GPIIb and GPIIIa, whereas knockdown of ASH1 in haematopoietic stem cells in vivo results in decreased number of macrophages and granulocytes
malfunction
cells lacking the enzyme display microsatellite instability and an elevated spontaneous mutation frequency, characteristic of DNA mismatch repair-deficient cells. Enzyme-deficient cells fail to recruit MutSalpha to chromatin
malfunction
enzyme downregulation leads to higher RNA polymerase II turnover at the transcription site and leads to intragenic transcription initiation in human cells
malfunction
enzyme knockdown in human endothelial cells impairs migration and tubule formation activities
malfunction
enzyme knockdown leads to defective repair of DNA double-strand breaks via the homologous recombination pathway
malfunction
enzyme knockdown significantly reduces survival after treatment with mitomycin C, camptothecin, or ionizing radiation in U2OS cells and HeLa cells
malfunction
enzyme loss is associated with alterations in mRNA splicing in human clear cell renal cell carcinoma
malfunction
enzyme silencing impairs the interaction between N6-methyladenosine methyltransferase complex proteins and their target mRNAs
physiological function
-
ASH1 regulates endogenous Hox gene expression positively and negatively and is required for myelomonocytic differentiation. ASH1 and MLL1 co-operate in Hox promoter activation
physiological function
histone H3 trimethylation at lysine 36 by the enzyme guides m6A RNA modification co-transcriptionally
physiological function
enzyme-dependent histone H3 lysine 36 trimethylation is required for homologous recombination repair and genome stability. The enzyme plays a presynaptic role for in homologous recombination, where it facilitates the recruitment of C-terminal binding protein interacting protein and promotes DNA double-strand break resection, allowing replication protein A and RAD51 binding to DNA damage sites
physiological function
enzyme-mediated histone H3 lysine 36 trimethylation is implicated in the regulation of alternative splicing and DNA mismatch repair
physiological function
the enzyme coordinates FACT complex-mediated exchange of histone H2B during transcription-coupled nucleosome displacement. The enzyme activity modulates FACT recruitment and nucleosome dynamics, thereby repressing cryptic transcription initiation
physiological function
the enzyme plays an important role in stimulating [histone H3]-N6,N6,N6-trimethyl-L-lysine36 at a specifically generated DNA double-strand breaks site
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). POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ubiquitination
the speckle-type POZ protein/cullin 3 complex polyubiquitinates and regulates the stability of the enzyme in vivo and in vitro
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
R1625C
the mutation results in a complete loss of histone H3 lysine 36 trimethylation activity. The mutant shows unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail
R2510H
the mutation does not result in an observable defect in enzymatic function
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Hi-Trap column chromatography, Source30Q column chromatography, and Superdex S200 gel filtration
Ni-NTA bead chromatography, glutathione bead chromatography, and Superdex 200 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
GST-SET domain fusion proteins are expressed in Escherichia coli, SET2-C is expressed in baculovirus insect cells
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Xie, P.; Tian, C.; An, L.; Nie, J.; Lu, K.; Xing, G.; Zhang, L.; He, F.
Histone methyltransferase protein SETD2 interacts with p53 and selectively regulates its downstream genes
Cell. Signal.
20
1671-1678
2008
Homo sapiens
Li, Y.; Trojer, P.; Xu, C.F.; Cheung, P.; Kuo, A.; Drury, W.J.; Qiao, Q.; Neubert, T.A.; Xu, R.M.; Gozani, O.; Reinberg, D.
The target of the NSD family of histone lysine methyltransferases depends on the nature of the substrate
J. Biol. Chem.
284
34283-34295
2009
Homo sapiens (O96028), Homo sapiens (Q9BYW2), Homo sapiens
Tanaka, Y.; Kawahashi, K.; Katagiri, Z.; Nakayama, Y.; Mahajan, M.; Kioussis, D.
Dual function of histone H3 lysine 36 methyltransferase ASH1 in regulation of Hox gene expression
PLoS ONE
6
e28171
2011
Homo sapiens
Eram, M.S.; Kuznetsova, E.; Li, F.; Lima-Fernandes, E.; Kennedy, S.; Chau, I.; Arrowsmith, C.H.; Schapira, M.; Vedadi, M.
Kinetic characterization of human histone H3 lysine 36 methyltransferases, ASH1L and SETD2
Biochim. Biophys. Acta
1850
1842-1848
2015
Homo sapiens (Q9BYW2)
Li, F.; Mao, G.; Tong, D.; Huang, J.; Gu, L.; Yang, W.; Li, G.M.
The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha
Cell
153
590-600
2013
Homo sapiens (Q9BYW2), Homo sapiens
Pfister, S.X.; Ahrabi, S.; Zalmas, L.P.; Sarkar, S.; Aymard, F.; Bachrati, C.Z.; Helleday, T.; Legube, G.; La Thangue, N.B.; Porter, A.C.; Humphrey, T.C.
SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability
Cell Rep.
7
2006-2018
2014
Homo sapiens (Q9BYW2)
Eram, M.S.; Bustos, S.P.; Lima-Fernandes, E.; Siarheyeva, A.; Senisterra, G.; Hajian, T.; Chau, I.; Duan, S.; Wu, H.; Dombrovski, L.; Schapira, M.; Arrowsmith, C.H.; Vedadi, M.
Trimethylation of histone H3 lysine 36 by human methyltransferase PRDM9 protein
J. Biol. Chem.
289
12177-12188
2014
Homo sapiens (Q9NQV7)
Hacker, K.E.; Fahey, C.C.; Shinsky, S.A.; Chiang, Y.J.; DiFiore, J.V.; Jha, D.K.; Vo, A.H.; Shavit, J.A.; Davis, I.J.; Strahl, B.D.; Rathmell, W.K.
Structure/function analysis of recurrent mutations in SETD2 protein reveals a critical and conserved role for a SET domain residue in maintaining protein stability and histone H3 Lys-36 trimethylation
J. Biol. Chem.
291
21283-21295
2016
Saccharomyces cerevisiae (P46995), Homo sapiens (Q9BYW2)
Li, L.; Wang, Y.
Cross-talk between the H3K36me3 and H4K16ac histone epigenetic marks in DNA double-strand break repair
J. Biol. Chem.
292
11951-11959
2017
Homo sapiens (Q9BYW2)
Huang, H.; Weng, H.; Zhou, K.; Wu, T.; Zhao, B.S.; Sun, M.; Chen, Z.; Deng, X.; Xiao, G.; Auer, F.; Klemm, L.; Wu, H.; Zuo, Z.; Qin, X.; Dong, Y.; Zhou, Y.; Qin, H.; Tao, S.; Du, J.; Liu, J.; Lu, Z.; Yin, H.; Mesquita, A.; Yuan, C.L.; Hu, Y.C.; Sun, W.; Su, R.; Dong, L.; Shen, C.; Li, C.; Qing, Y.; Jiang, X.; Wu, X.; Sun, M.
Histone H3 trimethylation at lysine 36 guides m6A RNA modification co-transcriptionally
Nature
567
414-419
2019
Homo sapiens (Q9BYW2)
Carvalho, S.; Raposo, A.C.; Martins, F.B.; Grosso, A.R.; Sridhara, S.C.; Rino, J.; Carmo-Fonseca, M.; de Almeida, S.F.
Histone methyltransferase SETD2 coordinates FACT recruitment with nucleosome dynamics during transcription
Nucleic Acids Res.
41
2881-2893
2013
Homo sapiens (Q9BYW2)
Zhu, K.; Lei, P.J.; Ju, L.G.; Wang, X.; Huang, K.; Yang, B.; Shao, C.; Zhu, Y.; Wei, G.; Fu, X.D.; Li, L.; Wu, M.
SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing
Nucleic Acids Res.
45
92-105
2017
Homo sapiens (Q9BYW2)
Ho, T.H.; Park, I.Y.; Zhao, H.; Tong, P.; Champion, M.D.; Yan, H.; Monzon, F.A.; Hoang, A.; Tamboli, P.; Parker, A.S.; Joseph, R.W.; Qiao, W.; Dykema, K.; Tannir, N.M.; Castle, E.P.; Nunez-Nateras, R.; Teh, B.T.; Wang, J.; Walker, C.L.; Hung, M.C.; Jonasch, E.
High-resolution profiling of histone h3 lysine 36 trimethylation in metastatic renal cell carcinoma
Oncogene
35
1565-1574
2016
Homo sapiens (Q9BYW2)
Hu, M.; Sun, X.J.; Zhang, Y.L.; Kuang, Y.; Hu, C.Q.; Wu, W.L.; Shen, S.H.; Du, T.T.; Li, H.; He, F.; Xiao, H.S.; Wang, Z.G.; Liu, T.X.; Lu, H.; Huang, Q.H.; Chen, S.J.; Chen, Z.
Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling
Proc. Natl. Acad. Sci. USA
107
2956-2961
2010
Mus musculus (E9Q5F9), Homo sapiens (Q9BYW2)
EXTERNAL LINKS (specific for EC-Number 2.1.1.359)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
