Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG3VKPS)

• DOT Name: m7GpppN-mRNA hydrolase (DCP2)
• Synonyms: EC 3.6.1.62; Nucleoside diphosphate-linked moiety X motif 20; Nudix motif 20; mRNA-decapping enzyme 2; hDpc
• Gene Name: DCP2
• UniProt ID: DCP2_HUMAN
• PDB ID: 5MP0; 5QOH; 5QOI; 5QOJ; 5QOK; 5QOL; 5QOM; 5QON; 5QOO; 5QOP; 5QOQ; 5QOR; 5QOS; 5QOT; 5QOU; 5QOV; 5QOW; 5QOX; 5QOY; 5QOZ; 5QP0; 5QP1; 5QP2; 5QP3; 5QP4; 5QP5; 5QP6; 5QP7; 5QP8; 5QP9; 5QPA; 5QPB; 5QPC
• EC Number: 3.6.1.62
• Pfam ID: PF05026 ; PF00293
• Sequence:
  METKRVEIPGSVLDDLCSRFILHIPSEERDNAIRVCFQIELAHWFYLDFYMQNTPGLPQC
  GIRDFAKAVFSHCPFLLPQGEDVEKVLDEWKEYKMGVPTYGAIILDETLENVLLVQGYLA
  KSGWGFPKGKVNKEEAPHDCAAREVFEETGFDIKDYICKDDYIELRINDQLARLYIIPGI
  PKDTKFNPKTRREIRNIEWFSIEKLPCHRNDMTPKSKLGLAPNKFFMAIPFIRPLRDWLS
  RRFGDSSDSDNGFSSTGSTPAKPTVEKLSRTKFRHSQQLFPDGSPGDQWVKHRQPLQQKP
  YNNHSEMSDLLKGKNQSMRGNGRKQYQDSPNQKKRTNGLQPAKQQNSLMKCEKKLHPRKL
  QDNFETDAVYDLPSSSEDQLLEHAEGQPVACNGHCKFPFSSRAFLSFKFDHNAIMKILDL
• Function: Decapping metalloenzyme that catalyzes the cleavage of the cap structure on mRNAs. Removes the 7-methyl guanine cap structure from mRNA molecules, yielding a 5'-phosphorylated mRNA fragment and 7m-GDP. Necessary for the degradation of mRNAs, both in normal mRNA turnover and in nonsense-mediated mRNA decay. Plays a role in replication-dependent histone mRNA degradation. Has higher activity towards mRNAs that lack a poly(A) tail. Has no activity towards a cap structure lacking an RNA moiety. The presence of a N(6)-methyladenosine methylation at the second transcribed position of mRNAs (N(6),2'-O-dimethyladenosine cap; m6A(m)) provides resistance to DCP2-mediated decapping. Blocks autophagy in nutrient-rich conditions by repressing the expression of ATG-related genes through degradation of their transcripts.
• Tissue Specificity: Expressed in brain and testis. Not detected in heart (at protein level).
• KEGG Pathway: R. degradation (hsa03018)
• Reactome Pathway:
  mRNA decay by 5' to 3' exoribonuclease (R-HSA-430039)
  Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA (R-HSA-450385)
  Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA (R-HSA-450513)
  KSRP (KHSRP) binds and destabilizes mRNA (R-HSA-450604)
  ATF4 activates genes in response to endoplasmic reticulum stress (R-HSA-380994)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	m7GpppN-mRNA hydrolase (DCP2) increases the response to substance of Arsenic trioxide.	[9]
Methotrexate	DM2TEOL	Approved	m7GpppN-mRNA hydrolase (DCP2) affects the response to substance of Methotrexate.	[10]

3 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 m7GpppN-mRNA hydrolase (DCP2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of m7GpppN-mRNA hydrolase (DCP2).	[4]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of m7GpppN-mRNA hydrolase (DCP2).	[7]

5 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 m7GpppN-mRNA hydrolase (DCP2).	[2]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of m7GpppN-mRNA hydrolase (DCP2).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of m7GpppN-mRNA hydrolase (DCP2).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of m7GpppN-mRNA hydrolase (DCP2).	[6]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of m7GpppN-mRNA hydrolase (DCP2).	[8]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
• [10] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.