Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSYF511)

• DOT Name: Terminal nucleotidyltransferase 5A (TENT5A)
• Synonyms: EC 2.7.7.19; HBV X-transactivated gene 11 protein; HBV XAg-transactivated protein 11
• Gene Name: TENT5A
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Glioma
  Knee osteoarthritis
  Non-small-cell lung cancer
  Osteoarthritis
  Osteogenesis imperfecta type 3
  Osteogenesis imperfecta, type 18
  Retinitis pigmentosa
  Coronary heart disease
  Retinopathy
  Osteogenesis imperfecta
  Tuberculosis
  Colorectal adenoma
• UniProt ID: TET5A_HUMAN
• PDB ID: 8EXE; 8EXF
• EC Number: 2.7.7.19
• Pfam ID: PF07984
• Sequence:
  MAEGEGYFAMSEDELACSPYIPLGGDFGGGDFGGGDFGGGDFGGGGSFGGHCLDYCESPT
  AHCNVLNWEQVQRLDGILSETIPIHGRGNFPTLELQPSLIVKVVRRRLAEKRIGVRDVRL
  NGSAASHVLHQDSGLGYKDLDLIFCADLRGEGEFQTVKDVVLDCLLDFLPEGVNKEKITP
  LTLKEAYVQKMVKVCNDSDRWSLISLSNNSGKNVELKFVDSLRRQFEFSVDSFQIKLDSL
  LLFYECSENPMTETFHPTIIGESVYGDFQEAFDHLCNKIIATRNPEEIRGGGLLKYCNLL
  VRGFRPASDEIKTLQRYMCSRFFIDFSDIGEQQRKLESYLQNHFVGLEDRKYEYLMTLHG
  VVNESTVCLMGHERRQTLNLITMLAIRVLADQNVIPNVANVTCYYQPAPYVADANFSNYY
  IAQVQPVFTCQQQTYSTWLPCN
• Function: Cytoplasmic non-canonical poly(A) RNA polymerase that catalyzes the transfer of one adenosine molecule from an ATP to an mRNA poly(A) tail bearing a 3'-OH terminal group and participates in the cytoplasmic polyadenylation. Polyadenylates mRNA encoding extracellular matrix constituents and other genes crucial for bone mineralization and during osteoblast mineralization, mainly focuses on ER-targeted mRNAs.
• Tissue Specificity: Widely expressed, with preferential expression observed in the retina compared to other ocular tissues . Also expressed in osteoblasts .

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Knee osteoarthritis	DISLSNBJ	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[5]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[4]
Osteogenesis imperfecta type 3	DISFJVSJ	Strong	Genetic Variation	[6]
Osteogenesis imperfecta, type 18	DISHRP21	Strong	Autosomal recessive	[7]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[9]
Retinopathy	DISB4B0F	moderate	Biomarker	[10]
Osteogenesis imperfecta	DIS7XQSD	Supportive	Autosomal dominant	[6]
Tuberculosis	DIS2YIMD	Disputed	Altered Expression	[11]
Colorectal adenoma	DISTSVHM	Limited	Altered Expression	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Terminal nucleotidyltransferase 5A (TENT5A) affects the response to substance of Etoposide.	[34]
Mitomycin	DMH0ZJE	Approved	Terminal nucleotidyltransferase 5A (TENT5A) affects the response to substance of Mitomycin.	[34]

23 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 Terminal nucleotidyltransferase 5A (TENT5A).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[22]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[23]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[24]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[25]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[27]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[29]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[31]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[32]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Terminal nucleotidyltransferase 5A (TENT5A).	[33]

References

• [1] Identification of the potential biomarkers in patients with glioma: a weighted gene co-expression network analysis.Carcinogenesis. 2020 Jul 10;41(6):743-750. doi: 10.1093/carcin/bgz194.
• [2] Evaluating genome-wide association study-identified breast cancer risk variants in African-American women.PLoS One. 2013 Apr 8;8(4):e58350. doi: 10.1371/journal.pone.0058350. Print 2013.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Susceptibility to large-joint osteoarthritis (hip and knee) is associated with BAG6 rs3117582 SNP and the VNTR polymorphism in the second exon of the FAM46A gene on chromosome 6.J Orthop Res. 2015 Jan;33(1):56-62. doi: 10.1002/jor.22738. Epub 2014 Sep 18.
• [5] Association of the FAM46A gene VNTRs and BAG6 rs3117582 SNP with non small cell lung cancer (NSCLC) in Croatian and Norwegian populations.PLoS One. 2015 Apr 17;10(4):e0122651. doi: 10.1371/journal.pone.0122651. eCollection 2015.
• [6] FAM46A mutations are responsible for autosomal recessive osteogenesis imperfecta. J Med Genet. 2018 Apr;55(4):278-284. doi: 10.1136/jmedgenet-2017-104999. Epub 2018 Jan 22.
• [7] [Meal-time training of children with cerebral palsy]. Kango Gijutsu. 1977 Dec;23(16):55-66.
• [8] Genetic analysis of FAM46A in Spanish families with autosomal recessive retinitis pigmentosa: characterisation of novel VNTRs.Ann Hum Genet. 2008 Jan;72(Pt 1):26-34. doi: 10.1111/j.1469-1809.2007.00393.x. Epub 2007 Sep 5.
• [9] Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.Nat Genet. 2018 Sep;50(9):1335-1341. doi: 10.1038/s41588-018-0184-y. Epub 2018 Aug 13.
• [10] Identification and characterization of C6orf37, a novel candidate human retinal disease gene on chromosome 6q14.Biochem Biophys Res Commun. 2002 Apr 26;293(1):356-65. doi: 10.1016/S0006-291X(02)00228-0.
• [11] Association of variable number of tandem repeats in the coding region of the FAM46A gene, FAM46A rs11040 SNP and BAG6 rs3117582 SNP with susceptibility to tuberculosis.PLoS One. 2014 Mar 13;9(3):e91385. doi: 10.1371/journal.pone.0091385. eCollection 2014.
• [12] Identification of a novel VNTR polymorphism in C6orf37 and its association with colorectal cancer risk in Chinese population.Clin Chim Acta. 2006 Jun;368(1-2):155-9. doi: 10.1016/j.cca.2005.12.043. Epub 2006 Mar 20.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] 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.
• [15] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [20] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [21] 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.
• [22] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [23] 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.
• [24] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [25] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [26] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] 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.
• [30] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [31] 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.
• [32] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [33] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [34] 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.