Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDTF5BU)

DOT Name Histone-lysine N-methyltransferase SUV39H1 (SUV39H1)
Synonyms EC 2.1.1.355; Histone H3-K9 methyltransferase 1; H3-K9-HMTase 1; Lysine N-methyltransferase 1A; Position-effect variegation 3-9 homolog; Suppressor of variegation 3-9 homolog 1; Su(var)3-9 homolog 1
Gene Name SUV39H1
UniProt ID
SUV91_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
3MTS
EC Number
2.1.1.355
Pfam ID
PF00385 ; PF05033 ; PF00856
Sequence
MAENLKGCSVCCKSSWNQLQDLCRLAKLSCPALGISKRNLYDFEVEYLCDYKKIREQEYY
LVKWRGYPDSESTWEPRQNLKCVRILKQFHKDLERELLRRHHRSKTPRHLDPSLANYLVQ
KAKQRRALRRWEQELNAKRSHLGRITVENEVDLDGPPRAFVYINEYRVGEGITLNQVAVG
CECQDCLWAPTGGCCPGASLHKFAYNDQGQVRLRAGLPIYECNSRCRCGYDCPNRVVQKG
IRYDLCIFRTDDGRGWGVRTLEKIRKNSFVMEYVGEIITSEEAERRGQIYDRQGATYLFD
LDYVEDVYTVDAAYYGNISHFVNHSCDPNLQVYNVFIDNLDERLPRIAFFATRTIRAGEE
LTFDYNMQVDPVDMESTRMDSNFGLAGLPGSPKKRVRIECKCGTESCRKYLF
Function
Histone methyltransferase that specifically trimethylates 'Lys-9' of histone H3 using monomethylated H3 'Lys-9' as substrate. Also weakly methylates histone H1 (in vitro). H3 'Lys-9' trimethylation represents a specific tag for epigenetic transcriptional repression by recruiting HP1 (CBX1, CBX3 and/or CBX5) proteins to methylated histones. Mainly functions in heterochromatin regions, thereby playing a central role in the establishment of constitutive heterochromatin at pericentric and telomere regions. H3 'Lys-9' trimethylation is also required to direct DNA methylation at pericentric repeats. SUV39H1 is targeted to histone H3 via its interaction with RB1 and is involved in many processes, such as repression of MYOD1-stimulated differentiation, regulation of the control switch for exiting the cell cycle and entering differentiation, repression by the PML-RARA fusion protein, BMP-induced repression, repression of switch recombination to IgA and regulation of telomere length. Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Recruited by the large PER complex to the E-box elements of the circadian target genes such as PER2 itself or PER1, contributes to the conversion of local chromatin to a heterochromatin-like repressive state through H3 'Lys-9' trimethylation; (Microbial infection) Plays a role in defense against mycobacterial infections. Methylates M.tuberculosis HupB on 'Lys-140', probably methylates HupB of M.bovis also. Methylation has an inhibitory effect on mycobacterial growth in the host. Macrophages expressing about 60% SUV39H1 are slightly more susceptible to M.bovis or M.tuberculosis infection. Chaetocin (an inhibitor of this enzyme) increases macrophage survival of M.tuberculosis. This protein inhibits biofilm formation by M.tuberculosis via 'Lys-140' trimethylation.
KEGG Pathway
Lysine degradation (hsa00310 )
Metabolic pathways (hsa01100 )
Reactome Pathway
SIRT1 negatively regulates rRNA expression (R-HSA-427359 )
PKMTs methylate histone lysines (R-HSA-3214841 )
BioCyc Pathway
MetaCyc:HS02321-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
26 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [1]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [2]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [3]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [4]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [5]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [6]
Calcitriol DM8ZVJ7 Approved Calcitriol decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [7]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [7]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [8]
Cannabidiol DM0659E Approved Cannabidiol decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [10]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [11]
Troglitazone DM3VFPD Approved Troglitazone decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [12]
Ethanol DMDRQZU Approved Ethanol increases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [13]
Diclofenac DMPIHLS Approved Diclofenac affects the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [8]
Camptothecin DM6CHNJ Phase 3 Camptothecin increases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [14]
Triptolide DMCMDVR Phase 3 Triptolide decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [15]
PEITC DMOMN31 Phase 2 PEITC decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [16]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [17]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [18]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [19]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [20]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [22]
Trichostatin A DM9C8NX Investigative Trichostatin A affects the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [23]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [24]
Deguelin DMXT7WG Investigative Deguelin decreases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [25]
DZNep DM0JXBK Investigative DZNep increases the expression of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [14]
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⏷ Show the Full List of 26 Drug(s)
3 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Fulvestrant DM0YZC6 Approved Fulvestrant increases the methylation of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [9]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [21]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of Histone-lysine N-methyltransferase SUV39H1 (SUV39H1). [21]
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References

1 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
2 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
3 Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
4 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
5 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
6 Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.
7 Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
8 Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
9 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
10 Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
11 Bortezomib induces caspase-dependent apoptosis in Hodgkin lymphoma cell lines and is associated with reduced c-FLIP expression: a gene expression profiling study with implications for potential combination therapies. Leuk Res. 2008 Feb;32(2):275-85. doi: 10.1016/j.leukres.2007.05.024. Epub 2007 Jul 19.
12 Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
13 Alcohol triggered bile acid disequilibrium by suppressing BSEP to sustain hepatocellular carcinoma progression. Chem Biol Interact. 2022 Apr 1;356:109847. doi: 10.1016/j.cbi.2022.109847. Epub 2022 Feb 9.
14 Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
15 Triptolide alters histone H3K9 and H3K27 methylation state and induces G0/G1 arrest and caspase-dependent apoptosis in multiple myeloma in vitro. Toxicology. 2010 Jan 12;267(1-3):70-9. doi: 10.1016/j.tox.2009.10.023. Epub 2009 Oct 29.
16 Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
17 Arsenic and benzo[a]pyrene co-exposure acts synergistically in inducing cancer stem cell-like property and tumorigenesis by epigenetically down-regulating SOCS3 expression. Environ Int. 2020 Apr;137:105560. doi: 10.1016/j.envint.2020.105560. Epub 2020 Feb 18.
18 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
19 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
20 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
21 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
22 Effects of BPA on global DNA methylation and global histone 3 lysine modifications in SH-SY5Y cells: An epigenetic mechanism linking the regulation of chromatin modifiying genes. Toxicol In Vitro. 2017 Oct;44:313-321. doi: 10.1016/j.tiv.2017.07.028. Epub 2017 Jul 29.
23 A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
24 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
25 Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.