Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3NCON3)

• DOT Name: mRNA-decapping enzyme 1A (DCP1A)
• Synonyms: EC 3.6.1.62; Smad4-interacting transcriptional co-activator; Transcription factor SMIF
• Gene Name: DCP1A
• Related Disease:
  Advanced cancer
  Lafora disease
  Colorectal carcinoma
  Gastric cancer
  Kaposi sarcoma
  Stomach cancer
  Melanoma
• UniProt ID: DCP1A_HUMAN
• PDB ID: 2WX3; 4B6H
• EC Number: 3.6.1.62
• Pfam ID: PF06058 ; PF16741
• Sequence:
  MEALSRAGQEMSLAALKQHDPYITSIADLTGQVALYTFCPKANQWEKTDIEGTLFVYRRS
  ASPYHGFTIVNRLNMHNLVEPVNKDLEFQLHEPFLLYRNASLSIYSIWFYDKNDCHRIAK
  LMADVVEEETRRSQQAARDKQSPSQANGCSDHRPIDILEMLSRAKDEYERNQMGDSNISS
  PGLQPSTQLSNLGSTETLEEMPSGSQDKSAPSGHKHLTVEELFGTSLPKEQPAVVGLDSE
  EMERLPGDASQKEPNSFLPFPFEQLGGAPQSETLGVPSAAHHSVQPEITTPVLITPASIT
  QSNEKHAPTYTIPLSPVLSPTLPAEAPTAQVPPSLPRNSTMMQAVKTTPRQRSPLLNQPV
  PELSHASLIANQSPFRAPLNVTNTAGTSLPSVDLLQKLRLTPQHDQIQTQPLGKGAMVAS
  FSPAAGQLATPESFIEPPSKTAAARVAASASLSNMVLAPLQSMQQNQDPEVFVQPKVLSS
  AIPVAGAPLVTATTTAVSSVLLAPSVFQQTVTRSSDLERKASSPSPLTIGTPESQRKPSI
  ILSKSQLQDTLIHLIKNDSSFLSTLHEVYLQVLTKNKDNHNL
• Function: Necessary for the degradation of mRNAs, both in normal mRNA turnover and in nonsense-mediated mRNA decay. Removes the 7-methyl guanine cap structure from mRNA molecules, yielding a 5'-phosphorylated mRNA fragment and 7m-GDP. Contributes to the transactivation of target genes after stimulation by TGFB1. Essential for embryonic development.
• Tissue Specificity: Detected in heart, brain, placenta, lung, skeletal muscle, liver, kidney and pancreas.
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA (R-HSA-450385)
  Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA (R-HSA-450513)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  mRNA decay by 5' to 3' exoribonuclease (R-HSA-430039)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Lafora disease	DIS83JHH	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[1]
Gastric cancer	DISXGOUK	Disputed	Biomarker	[3]
Kaposi sarcoma	DISC1H1Z	Disputed	Biomarker	[4]
Stomach cancer	DISKIJSX	Disputed	Biomarker	[3]
Melanoma	DIS1RRCY	Limited	Altered Expression	[5]

6 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 mRNA-decapping enzyme 1A (DCP1A).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of mRNA-decapping enzyme 1A (DCP1A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of mRNA-decapping enzyme 1A (DCP1A).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of mRNA-decapping enzyme 1A (DCP1A).	[10]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of mRNA-decapping enzyme 1A (DCP1A).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of mRNA-decapping enzyme 1A (DCP1A).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of mRNA-decapping enzyme 1A (DCP1A).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of mRNA-decapping enzyme 1A (DCP1A).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of mRNA-decapping enzyme 1A (DCP1A).	[9]

References

• [1] MALAT1 promotes the colorectal cancer malignancy by increasing DCP1A expression and miR203 downregulation.Mol Carcinog. 2018 Oct;57(10):1421-1431. doi: 10.1002/mc.22868. Epub 2018 Jul 12.
• [2] Lafora disease E3 ubiquitin ligase malin is recruited to the processing bodies and regulates the microRNA-mediated gene silencing process via the decapping enzyme Dcp1a.RNA Biol. 2012 Dec;9(12):1440-9. doi: 10.4161/rna.22708. Epub 2012 Nov 6.
• [3] LINC00339 promotes gastric cancer progression by elevating DCP1A expression via inhibiting miR-377-3p.J Cell Physiol. 2019 Dec;234(12):23667-23674. doi: 10.1002/jcp.28934. Epub 2019 Jun 12.
• [4] KSHV RNA-binding protein ORF57 inhibits P-body formation to promote viral multiplication by interaction with Ago2 and GW182.Nucleic Acids Res. 2019 Sep 26;47(17):9368-9385. doi: 10.1093/nar/gkz683.
• [5] Overexpression of mRNA-decapping enzyme 1a predicts disease-specific survival in malignant melanoma.Melanoma Res. 2018 Feb;28(1):30-36. doi: 10.1097/CMR.0000000000000406.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.