Details of Drug Off-Target (DOT)

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

• DOT Name: Oligoribonuclease, mitochondrial (REXO2)
• Synonyms: EC 3.1.15.-; RNA exonuclease 2 homolog; Small fragment nuclease
• Gene Name: REXO2
• Related Disease:
  Inflammatory bowel disease
  Lung adenocarcinoma
  Sporadic pheochromocytoma
• UniProt ID: ORN_HUMAN
• PDB ID: 6J7Y; 6J7Z; 6J80; 6N6I; 6N6J; 6N6K; 6RCI; 6RCL; 6RCN; 6STY
• EC Number: 3.1.15.-
• Pfam ID: PF00929
• Sequence:
  MLGGSLGSRLLRGVGGSHGRFGARGVREGGAAMAAGESMAQRMVWVDLEMTGLDIEKDQI
  IEMACLITDSDLNILAEGPNLIIKQPDELLDSMSDWCKEHHGKSGLTKAVKESTITLQQA
  EYEFLSFVRQQTPPGLCPLAGNSVHEDKKFLDKYMPQFMKHLHYRIIDVSTVKELCRRWY
  PEEYEFAPKKAASHRALDDISESIKELQFYRNNIFKKKIDEKKRKIIENGENEKTVS
• Function: 3'-to-5'exoribonuclease that preferentially degrades DNA and RNA oligonucleotides composed of only two nucleotides. Binds and degrades longer oligonucleotides with a lower affinity. Plays dual roles in mitochondria, scavenging nanoRNAs (small RNA oligonucleotides of <5 nucleotides) that are produced by the degradosome and clearing short RNAs that are generated by RNA processing. Essential for correct initiation of mitochondrial transcription, degrading mitochondrial RNA dinucleotides to prevent RNA-primed transcription at non-canonical sites in the mitochondrial genome. Essential for embryonic development; [Isoform 3]: 3'-to-5'exoribonuclease that preferentially degrades DNA and RNA oligonucleotides composed of only two nucleotides.
• Tissue Specificity: Highly expressed in the heart and at lower levels in the lymph nodes, brain, lung, liver, spleen and thymus.
• KEGG Pathway: Ribosome biogenesis in eukaryotes (hsa03008)
• Reactome Pathway: Mitochondrial RNA degradation (R-HSA-9836573)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Sporadic pheochromocytoma	DISQWTMO	Limited	Autosomal dominant	[3]

2 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 Oligoribonuclease, mitochondrial (REXO2).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Oligoribonuclease, mitochondrial (REXO2).	[13]

11 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 Oligoribonuclease, mitochondrial (REXO2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Oligoribonuclease, mitochondrial (REXO2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Oligoribonuclease, mitochondrial (REXO2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Oligoribonuclease, mitochondrial (REXO2).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Oligoribonuclease, mitochondrial (REXO2).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Oligoribonuclease, mitochondrial (REXO2).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Oligoribonuclease, mitochondrial (REXO2).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Oligoribonuclease, mitochondrial (REXO2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Oligoribonuclease, mitochondrial (REXO2).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Oligoribonuclease, mitochondrial (REXO2).	[15]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Oligoribonuclease, mitochondrial (REXO2).	[16]

References

• [1] Enrichment of inflammatory bowel disease and colorectal cancer risk variants in colon expression quantitative trait loci.BMC Genomics. 2015 Feb 27;16(1):138. doi: 10.1186/s12864-015-1292-z.
• [2] Low BIK outside-inside-out interactive inflammation immune-induced transcription-dependent apoptosis through FUT3-PMM2-SQSTM1-SFN-ZNF384.Immunol Res. 2016 Apr;64(2):461-9. doi: 10.1007/s12026-015-8701-x.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] 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.
• [5] 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.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] 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.
• [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] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [16] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.