Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHY50SK)

• DOT Name: THO complex subunit 5 homolog (THOC5)
• Synonyms: Functional spliceosome-associated protein 79; fSAP79; NF2/meningioma region protein pK1.3; Placental protein 39.2; PP39.2; hTREX90
• Gene Name: THOC5
• Related Disease:
  Anemia
  Beta thalassemia
  Hepatocellular carcinoma
  Leukemia
  Neoplasm
  Advanced cancer
  Darier disease
  Diastrophic dysplasia
  Vascular disease
• UniProt ID: THOC5_HUMAN
• PDB ID: 7APK; 7ZNK; 7ZNL
• Pfam ID: PF09766
• Sequence:
  MSSESSKKRKPKVIRSDGAPAEGKRNRSDTEQEGKYYSEEAEVDLRDPGRDYELYKYTCQ
  ELQRLMAEIQDLKSRGGKDVAIEIEERRIQSCVHFMTLKKLNRLAHIRLKKGRDQTHEAK
  QKVDAYHLQLQNLLYEVMHLQKEITKCLEFKSKHEEIDLVSLEEFYKEAPPDISKAEVTM
  GDPHQQTLARLDWELEQRKRLAEKYRECLSNKEKILKEIEVKKEYLSSLQPRLNSIMQAS
  LPVQEYLFMPFDQAHKQYETARHLPPPLYVLFVQATAYGQACDKTLSVAIEGSVDEAKAL
  FKPPEDSQDDESDSDAEEEQTTKRRRPTLGVQLDDKRKEMLKRHPLSVMLDLKCKDDSVL
  HLTFYYLMNLNIMTVKAKVTTAMELITPISAGDLLSPDSVLSCLYPGDHGKKTPNPANQY
  QFDKVGILTLSDYVLELGHPYLWVQKLGGLHFPKEQPQQTVIADHSLSASHMETTMKLLK
  TRVQSRLALHKQFASLEHGIVPVTSDCQYLFPAKVVSRLVKWVTVAHEDYMELHFTKDIV
  DAGLAGDTNLYYMALIERGTAKLQAAVVLNPGYSSIPPVFQLCLNWKGEKTNSNDDNIRA
  MEGEVNVCYKELCGPWPSHQLLTNQLQRLCVLLDVYLETESHDDSVEGPKEFPQEKMCLR
  LFRGPSRMKPFKYNHPQGFFSHR
• Function: Acts as a component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which 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 via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. THOC5 in conjunction with ALYREF/THOC4 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 transcription elongation and genome stability. Involved in alternative polyadenylation site choice by recruiting CPSF6 to 5' region of target genes; probably mediates association of the TREX and CFIm complexes.; Regulates the expression of myeloid transcription factors CEBPA, CEBPB and GAB2 by enhancing the levels of phosphatidylinositol 3,4,5-trisphosphate. May be involved in the differentiation of granulocytes and adipocytes. Essential for hematopoietic primitive cell survival and plays an integral role in monocytic development.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Biomarker	[1]
Beta thalassemia	DIS5RCQK	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Leukemia	DISNAKFL	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Darier disease	DIS4WI7S	Limited	Altered Expression	[5]
Diastrophic dysplasia	DISNTGP7	Limited	Altered Expression	[5]
Vascular disease	DISVS67S	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of THO complex subunit 5 homolog (THOC5).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of THO complex subunit 5 homolog (THOC5).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of THO complex subunit 5 homolog (THOC5).	[8]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of THO complex subunit 5 homolog (THOC5).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of THO complex subunit 5 homolog (THOC5).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of THO complex subunit 5 homolog (THOC5).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of THO complex subunit 5 homolog (THOC5).	[9]

References

• [1] Colla corii asini might upregulate ZNF471 and THOC5 by KRAB domain-containing zinc-finger protein pathway and THO complex subunit 5 pathway to improve anemia of pregnant women with -thalassemia.Ann Hematol. 2019 Aug;98(8):1813-1826. doi: 10.1007/s00277-019-03710-1. Epub 2019 May 16.
• [2] Depletion of three combined THOC5 mRNA export protein target genes synergistically induces human hepatocellular carcinoma cell death.Oncogene. 2016 Jul 21;35(29):3872-9. doi: 10.1038/onc.2015.433. Epub 2015 Nov 9.
• [3] A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5.Leukemia. 2013 Apr;27(4):932-40. doi: 10.1038/leu.2012.283. Epub 2012 Oct 3.
• [4] mRNA export protein THOC5 as a tool for identification of target genes for cancer therapy.Cancer Lett. 2016 Apr 10;373(2):222-6. doi: 10.1016/j.canlet.2016.01.045. Epub 2016 Jan 28.
• [5] THO Complex-Dependent Posttranscriptional Control Contributes to Vascular Smooth Muscle Cell Fate Decision.Circ Res. 2018 Aug 17;123(5):538-549. doi: 10.1161/CIRCRESAHA.118.313527.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.