Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOF2ADD)

• DOT Name: THO complex subunit 4 (ALYREF)
• Synonyms: Tho4; Ally of AML-1 and LEF-1; Aly/REF export factor; Transcriptional coactivator Aly/REF; bZIP-enhancing factor BEF
• Gene Name: ALYREF
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Depression
  HIV infectious disease
  Influenza
  Lung neoplasm
  Neoplasm
  Amyotrophic lateral sclerosis
  Hereditary breast ovarian cancer syndrome
  Squamous cell carcinoma
  Anxiety
  Anxiety disorder
  Frontotemporal dementia
  Psychotic disorder
  Schizophrenia
  Type-1 diabetes
• UniProt ID: THOC4_HUMAN
• PDB ID: 3ULH; 7ZNJ; 7ZNK
• Pfam ID: PF13865 ; PF00076
• Sequence:
  MADKMDMSLDDIIKLNRSQRGGRGGGRGRGRAGSQGGRGGGAQAAARVNRGGGPIRNRPA
  IARGAAGGGGRNRPAPYSRPKQLPDKWQHDLFDSGFGGGAGVETGGKLLVSNLDFGVSDA
  DIQELFAEFGTLKKAAVHYDRSGRSLGTADVHFERKADALKAMKQYNGVPLDGRPMNIQL
  VTSQIDAQRRPAQSVNRGGMTRNRGAGGFGGGGGTRRGTRGGARGRGRGAGRNSKQQLSA
  EELDAQLDAYNARMDTS
• Function: Export adapter involved in nuclear export of spliced and unspliced mRNA. Binds mRNA which is thought to be transferred to the NXF1-NXT1 heterodimer for export (TAP/NFX1 pathway). Component of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm. TREX recruitment occurs via an interaction between ALYREF/THOC4 and the cap-binding protein NCBP1. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production; ALYREF/THOC4 mediates the recruitment of the TREX complex to the intronless viral mRNA. Required for TREX complex assembly and for linking DDX39B to the cap-binding complex (CBC). In conjunction with THOC5 functions in NXF1-NXT1 mediated nuclear export of HSP70 mRNA; both proteins enhance the RNA binding activity of NXF1 and are required for NXF1 localization to the nuclear rim. Involved in the nuclear export of intronless mRNA; proposed to be recruited to intronless mRNA by ATP-bound DDX39B. Involved in transcription elongation and genome stability. Involved in mRNA export of C5-methylcytosine (m5C)-containing mRNAs: specifically recognizes and binds m5C mRNAs and mediates their nucleo-cytoplasmic shuttling ; Acts as a chaperone and promotes the dimerization of transcription factors containing basic leucine zipper (bZIP) domains and thereby promotes transcriptional activation.
• Tissue Specificity: Expressed in a wide variety of cancer types.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
  Spliceosome (hsa03040)
  Amyotrophic lateral sclerosis (hsa05014)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Depression	DIS3XJ69	Strong	Biomarker	[2]
HIV infectious disease	DISO97HC	Strong	Biomarker	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Amyotrophic lateral sclerosis	DISF7HVM	moderate	Biomarker	[7]
Hereditary breast ovarian cancer syndrome	DISWDUGU	moderate	Genetic Variation	[8]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[9]
Anxiety	DISIJDBA	Limited	Biomarker	[10]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[10]
Frontotemporal dementia	DISKYHXL	Limited	Biomarker	[7]
Psychotic disorder	DIS4UQOT	Limited	Biomarker	[11]
Schizophrenia	DISSRV2N	Limited	Biomarker	[11]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[12]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	THO complex subunit 4 (ALYREF) affects the response to substance of Acetaminophen.	[23]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of THO complex subunit 4 (ALYREF).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of THO complex subunit 4 (ALYREF).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of THO complex subunit 4 (ALYREF).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of THO complex subunit 4 (ALYREF).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of THO complex subunit 4 (ALYREF).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of THO complex subunit 4 (ALYREF).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of THO complex subunit 4 (ALYREF).	[17]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of THO complex subunit 4 (ALYREF).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of THO complex subunit 4 (ALYREF).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of THO complex subunit 4 (ALYREF).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of THO complex subunit 4 (ALYREF).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of THO complex subunit 4 (ALYREF).	[22]

References

• [1] Circulating microRNAs as candidate markers to distinguish heart failure in breathless patients.Eur J Heart Fail. 2013 Oct;15(10):1138-47. doi: 10.1093/eurjhf/hft078. Epub 2013 May 21.
• [2] The contribution of illness perceptions and metacognitive beliefs to anxiety and depression in adults with diabetes.Diabetes Res Clin Pract. 2018 Feb;136:16-22. doi: 10.1016/j.diabres.2017.11.029. Epub 2017 Dec 1.
• [3] Host cell gene expression during human immunodeficiency virus type 1 latency and reactivation and effects of targeting genes that are differentially expressed in viral latency.J Virol. 2004 Sep;78(17):9458-73. doi: 10.1128/JVI.78.17.9458-9473.2004.
• [4] Highly pathogenic avian influenza virus nucleoprotein interacts with TREX complex adaptor protein Aly/REF.PLoS One. 2013 Sep 20;8(9):e72429. doi: 10.1371/journal.pone.0072429. eCollection 2013.
• [5] Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers.BMC Cancer. 2011 Feb 17;11:77. doi: 10.1186/1471-2407-11-77.
• [6] Hyperprogressive Disease Is a New Pattern of Progression in Cancer Patients Treated by Anti-PD-1/PD-L1.Clin Cancer Res. 2017 Apr 15;23(8):1920-1928. doi: 10.1158/1078-0432.CCR-16-1741. Epub 2016 Nov 8.
• [7] Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies.Acta Neuropathol Commun. 2019 Apr 29;7(1):65. doi: 10.1186/s40478-019-0710-x.
• [8] Enhanced detection of mutations in BRCA1 exon 11 using restriction endonuclease fingerprinting-single-strand conformation polymorphism.J Mol Med (Berl). 2000;78(10):580-7. doi: 10.1007/s001090000147.
• [9] ALY as a potential contributor to metastasis in human oral squamous cell carcinoma.J Cancer Res Clin Oncol. 2013 Apr;139(4):585-94. doi: 10.1007/s00432-012-1361-5. Epub 2012 Dec 15.
• [10] What Comes First Metacognition or Negative Emotion? A Test of Temporal Precedence.Front Psychol. 2019 Nov 19;10:2507. doi: 10.3389/fpsyg.2019.02507. eCollection 2019.
• [11] Examining the structure of ideas of reference in clinical and community samples.Compr Psychiatry. 2019 Aug;93:48-55. doi: 10.1016/j.comppsych.2019.06.006. Epub 2019 Jul 3.
• [12] Metformin as add-on to intensive insulin therapy in type 1 diabetes mellitus.Diabetes Obes Metab. 2017 Oct;19(10):1463-1467. doi: 10.1111/dom.12948. Epub 2017 May 22.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.