Details of Drug Off-Target (DOT)

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

• DOT Name: 7SK snRNA methylphosphate capping enzyme (MEPCE)
• Synonyms: MePCE; EC 2.1.1.-; Bicoid-interacting protein 3 homolog; Bin3 homolog
• Gene Name: MEPCE
• Related Disease: Neurodevelopmental disorder
• UniProt ID: MEPCE_HUMAN
• PDB ID: 5UNA; 6DCB; 6DCC; 7SLP; 7SLQ
• EC Number: 2.1.1.-
• Pfam ID: PF06859
• Sequence:
  MIEMAAEKEPFLVPAPPPPLKDESGGGGGPTVPPHQEAASGELRGGTERGPGRCAPSAGS
  PAAAVGRESPGAAATSSSGPQAQQHRGGGPQAQSHGEARLSDPPGRAAPPDVGEERRGGG
  GTELGPPAPPRPRNGYQPHRPPGGGGGKRRNSCNVGGGGGGFKHPAFKRRRRVNSDCDSV
  LPSNFLLGGNIFDPLNLNSLLDEEVSRTLNAETPKSSPLPAKGRDPVEILIPKDITDPLS
  LNTCTDEGHVVLASPLKTGRKRHRHRGQHHQQQQAAGGSESHPVPPTAPLTPLLHGEGAS
  QQPRHRGQNRDAPQPYELNTAINCRDEVVSPLPSALQGPSGSLSAPPAASVISAPPSSSS
  RHRKRRRTSSKSEAGARGGGQGSKEKGRGSWGGRHHHHHPLPAAGFKKQQRKFQYGNYCK
  YYGYRNPSCEDGRLRVLKPEWFRGRDVLDLGCNVGHLTLSIACKWGPSRMVGLDIDSRLI
  HSARQNIRHYLSEELRLPPQTLEGDPGAEGEEGTTTVRKRSCFPASLTASRGPIAAPQVP
  LDGADTSVFPNNVVFVTGNYVLDRDDLVEAQTPEYDVVLCLSLTKWVHLNWGDEGLKRMF
  RRIYRHLRPGGILVLEPQPWSSYGKRKTLTETIYKNYYRIQLKPEQFSSYLTSPDVGFSS
  YELVATPHNTSKGFQRPVYLFHKARSPSH
• Function: S-adenosyl-L-methionine-dependent methyltransferase that adds a methylphosphate cap at the 5'-end of 7SK snRNA (7SK RNA), leading to stabilize it. Also has a non-enzymatic function as part of the 7SK RNP complex: the 7SK RNP complex sequesters the positive transcription elongation factor b (P-TEFb) in a large inactive 7SK RNP complex preventing RNA polymerase II phosphorylation and subsequent transcriptional elongation. The 7SK RNP complex also promotes snRNA gene transcription by RNA polymerase II via interaction with the little elongation complex (LEC). In the 7SK RNP complex, MEPCE is required to stabilize 7SK RNA and facilitate the assembly of 7SK RNP complex. MEPCE has a non-enzymatic function in the 7SK RNP complex; interaction with LARP7 within the 7SK RNP complex occluding its catalytic center.
• Tissue Specificity: Expressed in chronic myeloid leukemia cells, adrenal gland, brain, cerebellum, kidney, lung, mammary gland and testis . Weakly or not expressed in other tissues .

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[1]

7 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 7SK snRNA methylphosphate capping enzyme (MEPCE).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[7]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose increases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[8]
Bleomycin	DMNER5S	Approved	Bleomycin increases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[15]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[8]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide decreases the expression of 7SK snRNA methylphosphate capping enzyme (MEPCE).	[8]

References

• [1] de novo MEPCE nonsense variant associated with a neurodevelopmental disorder causes disintegration of 7SK snRNP and enhanced RNA polymerase II activation.Sci Rep. 2019 Aug 29;9(1):12516. doi: 10.1038/s41598-019-49032-0.
• [2] 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.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [14] 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.
• [15] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.