Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFDTNW4)

• DOT Name: Decapping and exoribonuclease protein (DXO)
• Synonyms: DXO; EC 3.6.1.-; 5'-3' exoribonuclease DXO; EC 3.1.13.-; Dom-3 homolog Z; NAD-capped RNA hydrolase DXO; DeNADding enzyme DXO; EC 3.6.1.-
• Gene Name: DXO
• Related Disease:
  Epilepsy
  Systemic lupus erythematosus
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: DXO_HUMAN
• EC Number: 3.1.13.-; 3.6.1.-
• Pfam ID: PF08652
• Sequence:
  MDPRGTKRGAEKTEVAEPRNKLPRPAPSLPTDPALYSGPFPFYRRPSELGCFSLDAQRQY
  HGDARALRYYSPPPTNGPGPNFDLRDGYPDRYQPRDEEVQERLDHLLCWLLEHRGRLEGG
  PGWLAEAIVTWRGHLTKLLTTPYERQEGWQLAASRFQGTLYLSEVETPNARAQRLARPPL
  LRELMYMGYKFEQYMCADKPGSSPDPSGEVNTNVAFCSVLRSRLGSHPLLFSGEVDCTDP
  QAPSTQPPTCYVELKTSKEMHSPGQWRSFYRHKLLKWWAQSFLPGVPNVVAGFRNPDGFV
  SSLKTFPTMKMFEYVRNDRDGWNPSVCMNFCAAFLSFAQSTVVQDDPRLVHLFSWEPGGP
  VTVSVHQDAPYAFLPIWYVEAMTQDLPSPPKTPSPK
• Function: Decapping enzyme for NAD-capped RNAs: specifically hydrolyzes the nicotinamide adenine dinucleotide (NAD) cap from a subset of RNAs by removing the entire NAD moiety from the 5'-end of an NAD-capped RNA. The NAD-cap is present at the 5'-end of some RNAs and snoRNAs. In contrast to the canonical 5'-end N7 methylguanosine (m7G) cap, the NAD cap promotes mRNA decay. Preferentially acts on NAD-capped transcripts in response to environmental stress. Also acts as a non-canonical decapping enzyme that removes the entire cap structure of m7G capped or incompletely capped RNAs and mediates their subsequent degradation. Specifically degrades pre-mRNAs with a defective 5'-end m7G cap and is part of a pre-mRNA capping quality control. Has decapping activity toward incomplete 5'-end m7G cap mRNAs such as unmethylated 5'-end-capped RNA (cap0), while it has no activity toward 2'-O-ribose methylated m7G cap (cap1). In contrast to canonical decapping enzymes DCP2 and NUDT16, which cleave the cap within the triphosphate linkage, the decapping activity releases the entire cap structure GpppN and a 5'-end monophosphate RNA. Also has 5'-3' exoribonuclease activities: The 5'-end monophosphate RNA is then degraded by the 5'-3' exoribonuclease activity, enabling this enzyme to decap and degrade incompletely capped mRNAs. Also possesses RNA 5'-pyrophosphohydrolase activity by hydrolyzing the 5'-end triphosphate to release pyrophosphates. Exhibits decapping activity towards FAD-capped RNAs. Exhibits decapping activity towards dpCoA-capped RNAs in vitro.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Biomarker	[1]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	moderate	Biomarker	[3]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Decapping and exoribonuclease protein (DXO).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Decapping and exoribonuclease protein (DXO).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Decapping and exoribonuclease protein (DXO).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Decapping and exoribonuclease protein (DXO).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Decapping and exoribonuclease protein (DXO).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Decapping and exoribonuclease protein (DXO).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Decapping and exoribonuclease protein (DXO).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Decapping and exoribonuclease protein (DXO).	[9]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Decapping and exoribonuclease protein (DXO).	[10]

References

• [1] IL-1-31/IL1-RA genetic markers association with idiopathic generalized epilepsy and treatment response in a cohort of Egyptian population.Int J Neurosci. 2020 Apr;130(4):348-354. doi: 10.1080/00207454.2019.1688809. Epub 2019 Nov 7.
• [2] Features of the two gene pairs RD-SKI2W and DOM3Z-RP1 located between complement component genes factor B and C4 at the MHC class III region.Front Biosci. 2001 Aug 1;6:D927-35. doi: 10.2741/yang.
• [3] Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA.Cancer Cell Int. 2019 May 30;19:149. doi: 10.1186/s12935-019-0874-2. eCollection 2019.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] Effect of ovarian steroids on gene expression profile in human uterine microvascular endothelial cells. Fertil Steril. 2009 Aug;92(2):709-21.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] 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.
• [9] 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.
• [10] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.