Details of Drug Off-Target (DOT)

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

• DOT Name: tRNA
• Synonyms: guanine-N(7)-)-methyltransferase non-catalytic subunit WDR4 (Protein Wuho homolog; hWH; WD repeat-containing protein 4
• Gene Name: WDR4
• Related Disease:
  Microcephaly, growth deficiency, seizures, and brain malformations
  Galloway-Mowat syndrome
  Galloway-Mowat syndrome 6
• UniProt ID: WDR4_HUMAN
• PDB ID: 7U20; 8CTH; 8CTI; 8D58; 8D9K; 8D9L; 8EG0; 8H0N
• Pfam ID: PF00400
• Sequence:
  MAGSVGLALCGQTLVVRGGSRFLATSIASSDDDSLFIYDCSAAEKKSQENKGEDAPLDQG
  SGAILASTFSKSGSYFALTDDSKRLILFRTKPWQCLSVRTVARRCTALTFIASEEKVLVA
  DKSGDVYSFSVLEPHGCGRLELGHLSMLLDVAVSPDDRFILTADRDEKIRVSWAAAPHSI
  ESFCLGHTEFVSRISVVPTQPGLLLSSSGDGTLRLWEYRSGRQLHCCHLASLQELVDPQA
  PQKFAASRIAFWCQENCVALLCDGTPVVYIFQLDARRQQLVYRQQLAFQHQVWDVAFEET
  QGLWVLQDCQEAPLVLYRPVGDQWQSVPESTVLKKVSGVLRGNWAMLEGSAGADASFSSL
  YKATFDNVTSYLKKKEERLQQQLEKKQRRRSPPPGPDGHAKKMRPGEATLSC
• Function: Non-catalytic component of the METTL1-WDR4 methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs). In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding. Required for the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop. M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay. Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs. Also required for methylation of a specific subset of miRNAs, such as let-7. Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcephaly, growth deficiency, seizures, and brain malformations	DISBAPYX	Strong	Autosomal recessive	[1]
Galloway-Mowat syndrome	DISVB7IM	Supportive	Autosomal recessive	[2]
Galloway-Mowat syndrome 6	DISZW5Z1	Limited	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of tRNA.	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of tRNA.	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of tRNA.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of tRNA.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of tRNA.	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of tRNA.	[8]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of tRNA.	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of tRNA.	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of tRNA.	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of tRNA.	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of tRNA.	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of tRNA.	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of tRNA.	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of tRNA.	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of tRNA.	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of tRNA.	[18]

References

• [1] Mutation in WDR4 impairs tRNA m(7)G46 methylation and causes a distinct form of microcephalic primordial dwarfism. Genome Biol. 2015 Sep 28;16:210. doi: 10.1186/s13059-015-0779-x.
• [2] Mutations in WDR4 as a new cause of Galloway-Mowat syndrome. Am J Med Genet A. 2018 Nov;176(11):2460-2465. doi: 10.1002/ajmg.a.40489. Epub 2018 Aug 6.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] 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.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [9] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
• [12] 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.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma. Int J Cancer. 2015 May 1;136(9):2055-64.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.