Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQW463T)

• DOT Name: Histone-lysine N-methyltransferase SETD2 (SETD2)
• Synonyms: EC 2.1.1.359; HIF-1; Huntingtin yeast partner B; Huntingtin-interacting protein 1; HIP-1; Huntingtin-interacting protein B; Lysine N-methyltransferase 3A; Protein-lysine N-methyltransferase SETD2; EC 2.1.1.-; SET domain-containing protein 2; hSET2; p231HBP
• Gene Name: SETD2
• Related Disease:
  SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth
  Luscan-Lumish syndrome
  Rabin-Pappas syndrome
  SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
  Sotos syndrome
• UniProt ID: SETD2_HUMAN
• PDB ID: 2A7O; 2MDC; 2MDI; 2MDJ; 4FMU; 4H12; 5JJY; 5JLB; 5JLE; 5LSS; 5LSX; 5LSY; 5LSZ; 5LT6; 5LT7; 5LT8; 5V21; 5V22; 6J9J; 6VDB; 7EA8; 7EVR; 7EVS; 7LZB; 7LZD; 7LZF; 7TY2; 7TY3
• EC Number: 2.1.1.-; 2.1.1.359
• Pfam ID: PF17907 ; PF00856 ; PF08236 ; PF00397
• Sequence:
  MKQLQPQPPPKMGDFYDPEHPTPEEEENEAKIENVQKTGFIKGPMFKGVASSRFLPKGTK
  TKVNLEEQGRQKVSFSFSLTKKTLQNRFLTALGNEKQSDTPNPPAVPLQVDSTPKMKMEI
  GDTLSTAEESSPPKSRVELGKIHFKKHLLHVTSRPLLATTTAVASPPTHAAPLPAVIAES
  TTVDSPPSSPPPPPPPAQATTLSSPAPVTEPVALPHTPITVLMAAPVPLPVDVAVRSLKE
  PPIIIVPESLEADTKQDTISNSLEEHVTQILNEQADISSKKEDSHIGKDEEIPDSSKISL
  SCKKTGSKKKSSQSEGIFLGSESDEDSVRTSSSQRSHDLKFSASIEKERDFKKSSAPLKS
  EDLGKPSRSKTDRDDKYFSYSKLERDTRYVSSRCRSERERRRSRSHSRSERGSRTNLSYS
  RSERSHYYDSDRRYHRSSPYRERTRYSRPYTDNRARESSDSEEEYKKTYSRRTSSHSSSY
  RDLRTSSYSKSDRDCKTETSYLEMERRGKYSSKLERESKRTSENEAIKRCCSPPNELGFR
  RGSSYSKHDSSASRYKSTLSKPIPKSDKFKNSFCCTELNEEIKQSHSFSLQTPCSKGSEL
  RMINKNPEREKAGSPAPSNRLNDSPTLKKLDELPIFKSEFITHDSHDSIKELDSLSKVKN
  DQLRSFCPIELNINGSPGAESDLATFCTSKTDAVLMTSDDSVTGSELSPLVKACMLSSNG
  FQNISRCKEKDLDDTCMLHKKSESPFRETEPLVSPHQDKLMSMPVMTVDYSKTVVKEPVD
  TRVSCCKTKDSDIYCTLNDSNPSLCNSEAENIEPSVMKISSNSFMNVHLESKPVICDSRN
  LTDHSKFACEEYKQSIGSTSSASVNHFDDLYQPIGSSGIASSLQSLPPGIKVDSLTLLKC
  GENTSPVLDAVLKSKKSSEFLKHAGKETIVEVGSDLPDSGKGFASRENRRNNGLSGKCLQ
  EAQEEGNSILPERRGRPEISLDERGEGGHVHTSDDSEVVFSSCDLNLTMEDSDGVTYALK
  CDSSGHAPEIVSTVHEDYSGSSESSNDESDSEDTDSDDSSIPRNRLQSVVVVPKNSTLPM
  EETSPCSSRSSQSYRHYSDHWEDERLESRRHLYEEKFESIASKACPQTDKFFLHKGTEKN
  PEISFTQSSRKQIDNRLPELSHPQSDGVDSTSHTDVKSDPLGHPNSEETVKAKIPSRQQE
  ELPIYSSDFEDVPNKSWQQTTFQNRPDSRLGKTELSFSSSCEIPHVDGLHSSEELRNLGW
  DFSQEKPSTTYQQPDSSYGACGGHKYQQNAEQYGGTRDYWQGNGYWDPRSGRPPGTGVVY
  DRTQGQVPDSLTDDREEEENWDQQDGSHFSDQSDKFLLSLQKDKGSVQAPEISSNSIKDT
  LAVNEKKDFSKNLEKNDIKDRGPLKKRRQEIESDSESDGELQDRKKVRVEVEQGETSVPP
  GSALVGPSCVMDDFRDPQRWKECAKQGKMPCYFDLIEENVYLTERKKNKSHRDIKRMQCE
  CTPLSKDERAQGEIACGEDCLNRLLMIECSSRCPNGDYCSNRRFQRKQHADVEVILTEKK
  GWGLRAAKDLPSNTFVLEYCGEVLDHKEFKARVKEYARNKNIHYYFMALKNDEIIDATQK
  GNCSRFMNHSCEPNCETQKWTVNGQLRVGFFTTKLVPSGSELTFDYQFQRYGKEAQKCFC
  GSANCRGYLGGENRVSIRAAGGKMKKERSRKKDSVDGELEALMENGEGLSDKNQVLSLSR
  LMVRIETLEQKLTCLELIQNTHSQSCLKSFLERHGLSLLWIWMAELGDGRESNQKLQEEI
  IKTLEHLPIPTKNMLEESKVLPIIQRWSQTKTAVPPLSEGDGYSSENTSRAHTPLNTPDP
  STKLSTEADTDTPKKLMFRRLKIISENSMDSAISDATSELEGKDGKEDLDQLENVPVEEE
  EELQSQQLLPQQLPECKVDSETNIEASKLPTSEPEADAEIEPKESNGTKLEEPINEETPS
  QDEEEGVSDVESERSQEQPDKTVDISDLATKLLDSWKDLKEVYRIPKKSQTEKENTTTER
  GRDAVGFRDQTPAPKTPNRSRERDPDKQTQNKEKRKRRSSLSPPSSAYERGTKRPDDRYD
  TPTSKKKVRIKDRNKLSTEERRKLFEQEVAQREAQKQQQQMQNLGMTSPLPYDSLGYNAP
  HHPFAGYPPGYPMQAYVDPSNPNAGKVLLPTPSMDPVCSPAPYDHAQPLVGHSTEPLSAP
  PPVPVVPHVAAPVEVSSSQYVAQSDGVVHQDSSVAVLPVPAPGPVQGQNYSVWDSNQQSV
  SVQQQYSPAQSQATIYYQGQTCPTVYGVTSPYSQTTPPIVQSYAQPSLQYIQGQQIFTAH
  PQGVVVQPAAAVTTIVAPGQPQPLQPSEMVVTNNLLDLPPPSPPKPKTIVLPPNWKTARD
  PEGKIYYYHVITRQTQWDPPTWESPGDDASLEHEAEMDLGTPTYDENPMKASKKPKTAEA
  DTSSELAKKSKEVFRKEMSQFIVQCLNPYRKPDCKVGRITTTEDFKHLARKLTHGVMNKE
  LKYCKNPEDLECNENVKHKTKEYIKKYMQKFGAVYKPKEDTELE
• Function: Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate. It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro. Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation. Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A. Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction. Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR). Acts as a tumor suppressor. H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A. H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase. Required during angiogenesis. Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3. In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1. Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling. Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription ; (Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Lysine degradation (hsa00310)
  Metabolic pathways (hsa01100)
• Reactome Pathway: PKMTs methylate histone lysines (R-HSA-3214841)
• BioCyc Pathway: MetaCyc:HS17695-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth	DIS3ENYF	Definitive	Autosomal dominant	[1]
Luscan-Lumish syndrome	DISHR74F	Strong	Autosomal dominant	[2]
Rabin-Pappas syndrome	DISKKZRN	Strong	Autosomal dominant	[3]
SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome	DISQSY1T	Strong	Autosomal dominant	[1]
Sotos syndrome	DISN4U1D	Supportive	Autosomal dominant	[4]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[10]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[14]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[9]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone-lysine N-methyltransferase SETD2 (SETD2).	[19]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Histone-lysine N-methyltransferase SETD2 (SETD2).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Histone-lysine N-methyltransferase SETD2 (SETD2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Histone-lysine N-methyltransferase SETD2 (SETD2).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Histone-lysine N-methyltransferase SETD2 (SETD2).	[16]

References

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• [2] Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012 Dec 21;338(6114):1619-22. doi: 10.1126/science.1227764. Epub 2012 Nov 15.
• [3] Genotype-phenotype correlation at codon 1740 of SETD2. Am J Med Genet A. 2020 Sep;182(9):2037-2048. doi: 10.1002/ajmg.a.61724. Epub 2020 Jul 24.
• [4] Mutations in SETD2 cause a novel overgrowth condition. J Med Genet. 2014 Aug;51(8):512-7. doi: 10.1136/jmedgenet-2014-102402. Epub 2014 May 22.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] 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.
• [8] Quantitative proteomic analysis of HepG2 cells treated with quercetin suggests IQGAP1 involved in quercetin-induced regulation of cell proliferation and migration. OMICS. 2009 Apr;13(2):93-103. doi: 10.1089/omi.2008.0075.
• [9] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [12] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [13] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [14] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] 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.
• [17] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.