Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG83E2C)

• DOT Name: Tudor domain-containing protein 3 (TDRD3)
• Gene Name: TDRD3
• Related Disease:
  Breast cancer
  Breast carcinoma
  Fragile X syndrome
  Neoplasm
• UniProt ID: TDRD3_HUMAN
• PDB ID: 1WJI; 2LTO; 3PMT; 3PNW; 3S6W; 5GVD; 5GVE; 5YJ8; 6V9T; 8JTN
• Pfam ID: PF08585 ; PF00567 ; PF00627
• Sequence:
  MLRLQMTDGHISCTAVEFSYMSKISLNTPPGTKVKLSGIVDIKNGFLLLNDSNTTVLGGE
  VEHLIEKWELQRSLSKHNRSNIGTEGGPPPFVPFGQKCVSHVQVDSRELDRRKTLQVTMP
  VKPTNDNDEFEKQRTAAIAEVAKSKETKTFGGGGGGARSNLNMNAAGNRNREVLQKEKST
  KSEGKHEGVYRELVDEKALKHITEMGFSKEASRQALMDNGNNLEAALNVLLTSNKQKPVM
  GPPLRGRGKGRGRIRSEDEEDLGNARPSAPSTLFDFLESKMGTLNVEEPKSQPQQLHQGQ
  YRSSNTEQNGVKDNNHLRHPPRNDTRQPRNEKPPRFQRDSQNSKSVLEGSGLPRNRGSER
  PSTSSVSEVWAEDRIKCDRPYSRYDRTKDTSYPLGSQHSDGAFKKRDNSMQSRSGKGPSF
  AEAKENPLPQGSVDYNNQKRGKRESQTSIPDYFYDRKSQTINNEAFSGIKIEKHFNVNTD
  YQNPVRSNSFIGVPNGEVEMPLKGRRIGPIKPAGPVTAVPCDDKIFYNSGPKRRSGPIKP
  EKILESSIPMEYAKMWKPGDECFALYWEDNKFYRAEVEALHSSGMTAVVKFIDYGNYEEV
  LLSNIKPIQTEAWEEEGTYDQTLEFRRGGDGQPRRSTRPTQQFYQPPRARN
• Function: Scaffolding protein that specifically recognizes and binds dimethylarginine-containing proteins. Plays a role in the regulation of translation of target mRNAs by binding Arg/Gly-rich motifs (GAR) in dimethylarginine-containing proteins. In nucleus, acts as a coactivator: recognizes and binds asymmetric dimethylation on the core histone tails associated with transcriptional activation (H3R17me2a and H4R3me2a) and recruits proteins at these arginine-methylated loci. In cytoplasm, acts as an antiviral factor that participates in the assembly of stress granules together with G3BP1.
• Tissue Specificity: Detected in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Fragile X syndrome	DISE8W3A	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Tudor domain-containing protein 3 (TDRD3) affects the response to substance of Etoposide.	[15]
Mitomycin	DMH0ZJE	Approved	Tudor domain-containing protein 3 (TDRD3) affects the response to substance of Mitomycin.	[15]

5 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 Tudor domain-containing protein 3 (TDRD3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Tudor domain-containing protein 3 (TDRD3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tudor domain-containing protein 3 (TDRD3).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Tudor domain-containing protein 3 (TDRD3).	[13]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Tudor domain-containing protein 3 (TDRD3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Tudor domain-containing protein 3 (TDRD3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tudor domain-containing protein 3 (TDRD3).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Tudor domain-containing protein 3 (TDRD3).	[8]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Tudor domain-containing protein 3 (TDRD3).	[14]

References

• [1] Tudor Domain Containing Protein 3 Promotes Tumorigenesis and Invasive Capacity of Breast Cancer Cells.Sci Rep. 2017 Jul 11;7(1):5153. doi: 10.1038/s41598-017-04955-4.
• [2] Tdrd3 is a novel stress granule-associated protein interacting with the Fragile-X syndrome protein FMRP.Hum Mol Genet. 2008 Oct 15;17(20):3236-46. doi: 10.1093/hmg/ddn219. Epub 2008 Jul 28.
• [3] 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.
• [4] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] 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.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] 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.