Details of Drug Off-Target (DOT)

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

• DOT Name: Histone-lysine N-methyltransferase SETD5 (SETD5)
• Synonyms: EC 2.1.1.359; EC 2.1.1.367; SET domain-containing protein 5
• Gene Name: SETD5
• Related Disease:
  Autism spectrum disorder
  Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
  Syndromic complex neurodevelopmental disorder
  Alcohol dependence
  Moyamoya disease
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Pervasive developmental disorder
  Vascular disease
  Cornelia de Lange syndrome
  Intellectual disability
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SETD5_HUMAN
• EC Number: 2.1.1.359; 2.1.1.367
• Pfam ID: PF00856
• Sequence:
  MSIAIPLGVTTSDTSYSDMAAGSDPESVEASPAVNEKSVYSTHNYGTTQRHGCRGLPYAT
  IIPRSDLNGLPSPVEERCGDSPNSEGETVPTWCPCGLSQDGFLLNCDKCRGMSRGKVIRL
  HRRKQDNISGGDSSATESWDEELSPSTVLYTATQHTPTSITLTVRRTKPKKRKKSPEKGR
  AAPKTKKIKNSPSEAQNLDENTTEGWENRIRLWTDQYEEAFTNQYSADVQNALEQHLHSS
  KEFVGKPTILDTINKTELACNNTVIGSQMQLQLGRVTRVQKHRKILRAARDLALDTLIIE
  YRGKVMLRQQFEVNGHFFKKPYPFVLFYSKFNGVEMCVDARTFGNDARFIRRSCTPNAEV
  RHMIADGMIHLCIYAVSAITKDAEVTIAFDYEYSNCNYKVDCACHKGNRNCPIQKRNPNA
  TELPLLPPPPSLPTIGAETRRRKARRKELEMEQQNEASEENNDQQSQEVPEKVTVSSDHE
  EVDNPEEKPEEEKEEVIDDQENLAHSRRTREDRKVEAIMHAFENLEKRKKRRDQPLEQSN
  SDVEITTTTSETPVGEETKTEAPESEVSNSVSNVTIPSTPQSVGVNTRRSSQAGDIAAEK
  LVPKPPPAKPSRPRPKSRISRYRTSSAQRLKRQKQANAQQAELSQAALEEGGSNSLVTPT
  EAGSLDSSGENRPLTGSDPTVVSITGSHVNRAASKYPKTKKYLVTEWLNDKAEKQECPVE
  CPLRITTDPTVLATTLNMLPGLIHSPLICTTPKHYIRFGSPFIPERRRRPLLPDGTFSSC
  KKRWIKQALEEGMTQTSSVPQETRTQHLYQSNENSSSSSICKDNADLLSPLKKWKSRYLM
  EQNVTKLLRPLSPVTPPPPNSGSKSPQLATPGSSHPGEEECRNGYSLMFSPVTSLTTASR
  CNTPLQFELCHRKDLDLAKVGYLDSNTNSCADRPSLLNSGHSDLAPHPSLGPTSETGFPS
  RSGDGHQTLVRNSDQAFRTEFNLMYAYSPLNAMPRADGLYRGSPLVGDRKPLHLDGGYCS
  PAEGFSSRYEHGLMKDLSRGSLSPGGERACEGVPSAPQNPPQRKKVSLLEYRKRKQEAKE
  NSAGGGGDSAQSKSKSAGAGQGSSNSVSDTGAHGVQGSSARTPSSPHKKFSPSHSSMSHL
  EAVSPSDSRGTSSSHCRPQENISSRWMVPTSVERLREGGSIPKVLRSSVRVAQKGEPSPT
  WESNITEKDSDPADGEGPETLSSALSKGATVYSPSRYSYQLLQCDSPRTESQSLLQQSSS
  PFRGHPTQSPGYSYRTTALRPGNPPSHGSSESSLSSTSYSSPAHPVSTDSLAPFTGTPGY
  FSSQPHSGNSTGSNLPRRSCPSSAASPTLQGPSDSPTSDSVSQSSTGTLSSTSFPQNSRS
  SLPSDLRTISLPSAGQSAVYQASRVSAVSNSQHYPHRGSGGVHQYRLQPLQGSGVKTQTG
  LS
• Function: Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission. May act by mediating trimethylation of 'Lys-36' of histone H3 (H3K36me3), which is essential to allow on-time RNA elongation dynamics. Also monomethylates 'Lys-9' of histone H3 (H3K9me1) in vitro. The relevance of histone methyltransferase activity is however subject to discussion.

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Definitive	Biomarker	[1]
Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	DISALM9J	Definitive	Autosomal dominant	[2]
Syndromic complex neurodevelopmental disorder	DISJ2RXI	Definitive	Autosomal dominant	[3]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[4]
Moyamoya disease	DISO62CA	Strong	Biomarker	[5]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Pervasive developmental disorder	DIS51975	Strong	Biomarker	[8]
Vascular disease	DISVS67S	Strong	Biomarker	[5]
Cornelia de Lange syndrome	DISEQSXO	moderate	GermlineCausalMutation	[9]
Intellectual disability	DISMBNXP	Limited	Biomarker	[1]
Prostate cancer	DISF190Y	Limited	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Histone-lysine N-methyltransferase SETD5 (SETD5).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Histone-lysine N-methyltransferase SETD5 (SETD5).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Histone-lysine N-methyltransferase SETD5 (SETD5).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Histone-lysine N-methyltransferase SETD5 (SETD5).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[17]
Marinol	DM70IK5	Approved	Marinol increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[21]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[22]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[28]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[29]
AHPN	DM8G6O4	Investigative	AHPN increases the expression of Histone-lysine N-methyltransferase SETD5 (SETD5).	[30]

References

• [1] Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.Transl Psychiatry. 2019 Jan 17;9(1):24. doi: 10.1038/s41398-018-0344-y.
• [2] Loss-of-function variants of SETD5 cause intellectual disability and the core phenotype of microdeletion 3p25.3 syndrome. Eur J Hum Genet. 2015 Jun;23(6):753-60. doi: 10.1038/ejhg.2014.165. Epub 2014 Aug 20.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] A novel, functional and replicable risk gene region for alcohol dependence identified by genome-wide association study.PLoS One. 2011;6(11):e26726. doi: 10.1371/journal.pone.0026726. Epub 2011 Nov 7.
• [5] The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.Genet Med. 2020 Feb;22(2):427-431. doi: 10.1038/s41436-019-0639-2. Epub 2019 Sep 2.
• [6] Genetic variations on SETD5 underlying autistic conditions.Dev Neurobiol. 2018 May;78(5):500-518. doi: 10.1002/dneu.22584. Epub 2018 Mar 5.
• [7] SET domain containing protein 5 (SETD5) enhances tumor cell invasion and is associated with a poor prognosis in non-small cell lung cancer patients.BMC Cancer. 2019 Jul 25;19(1):736. doi: 10.1186/s12885-019-5944-2.
• [8] Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition.Nat Neurosci. 2018 Dec;21(12):1717-1727. doi: 10.1038/s41593-018-0266-2. Epub 2018 Nov 19.
• [9] Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.Hum Genet. 2017 Mar;136(3):307-320. doi: 10.1007/s00439-017-1758-y. Epub 2017 Jan 24.
• [10] Identification of Novel Epigenetic Markers of Prostate Cancer by NotI-Microarray Analysis.Dis Markers. 2015;2015:241301. doi: 10.1155/2015/241301. Epub 2015 Sep 28.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] 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.
• [17] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [29] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [30] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.