Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNXE5G2)

DOT Name THO complex subunit 2 (THOC2)
Synonyms Tho2; hTREX120
Gene Name THOC2
Related Disease
X-linked intellectual disability ( )
Intellectual disability ( )
Melanoma ( )
X-linked intellectual disability-short stature-overweight syndrome ( )
UniProt ID
THOC2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7APK; 7ZNK; 7ZNL
Pfam ID
PF11262 ; PF11732 ; PF16134
Sequence
MAAAAVVVPAEWIKNWEKSGRGEFLHLCRILSENKSHDSSTYRDFQQALYELSYHVIKGN
LKHEQASNVLSDISEFREDMPSILADVFCILDIETNCLEEKSKRDYFTQLVLACLYLVSD
TVLKERLDPETLESLGLIKQSQQFNQKSVKIKTKLFYKQQKFNLLREENEGYAKLIAELG
QDLSGSITSDLILENIKSLIGCFNLDPNRVLDVILEVFECRPEHDDFFISLLESYMSMCE
PQTLCHILGFKFKFYQEPNGETPSSLYRVAAVLLQFNLIDLDDLYVHLLPADNCIMDEHK
REIAEAKQIVRKLTMVVLSSEKMDEREKEKEKEEEKVEKPPDNQKLGLLEALLKIGDWQH
AQNIMDQMPPYYAASHKLIALAICKLIHITIEPLYRRVGVPKGAKGSPVNALQNKRAPKQ
AESFEDLRRDVFNMFCYLGPHLSHDPILFAKVVRIGKSFMKEFQSDGSKQEDKEKTEVIL
SCLLSITDQVLLPSLSLMDCNACMSEELWGMFKTFPYQHRYRLYGQWKNETYNSHPLLVK
VKAQTIDRAKYIMKRLTKENVKPSGRQIGKLSHSNPTILFDYILSQIQKYDNLITPVVDS
LKYLTSLNYDVLAYCIIEALANPEKERMKHDDTTISSWLQSLASFCGAVFRKYPIDLAGL
LQYVANQLKAGKSFDLLILKEVVQKMAGIEITEEMTMEQLEAMTGGEQLKAEGGYFGQIR
NTKKSSQRLKDALLDHDLALPLCLLMAQQRNGVIFQEGGEKHLKLVGKLYDQCHDTLVQF
GGFLASNLSTEDYIKRVPSIDVLCNEFHTPHDAAFFLSRPMYAHHISSKYDELKKSEKGS
KQQHKVHKYITSCEMVMAPVHEAVVSLHVSKVWDDISPQFYATFWSLTMYDLAVPHTSYE
REVNKLKVQMKAIDDNQEMPPNKKKKEKERCTALQDKLLEEEKKQMEHVQRVLQRLKLEK
DNWLLAKSTKNETITKFLQLCIFPRCIFSAIDAVYCARFVELVHQQKTPNFSTLLCYDRV
FSDIIYTVASCTENEASRYGRFLCCMLETVTRWHSDRATYEKECGNYPGFLTILRATGFD
GGNKADQLDYENFRHVVHKWHYKLTKASVHCLETGEYTHIRNILIVLTKILPWYPKVLNL
GQALERRVHKICQEEKEKRPDLYALAMGYSGQLKSRKSYMIPENEFHHKDPPPRNAVASV
QNGPGGGPSSSSIGSASKSDESSTEETDKSRERSQCGVKAVNKASSTTPKGNSSNGNSGS
NSNKAVKENDKEKGKEKEKEKKEKTPATTPEARVLGKDGKEKPKEERPNKDEKARETKER
TPKSDKEKEKFKKEEKAKDEKFKTTVPNAESKSTQEREREKEPSRERDIAKEMKSKENVK
GGEKTPVSGSLKSPVPRSDIPEPEREQKRRKIDTHPSPSHSSTVKDSLIELKESSAKLYI
NHTPPPLSKSKEREMDKKDLDKSRERSREREKKDEKDRKERKRDHSNNDREVPPDLTKRR
KEENGTMGVSKHKSESPCESPYPNEKDKEKNKSKSSGKEKGSDSFKSEKMDKISSGGKKE
SRHDKEKIEKKEKRDSSGGKEEKKHHKSSDKHR
Function
Required for efficient export of polyadenylated RNA and spliced mRNA. 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. THOC2 (and probably the THO complex) is involved in releasing mRNA from nuclear speckle domains. Required for NXF1 localization to the nuclear rim. Plays a role for proper neuronal development.
Tissue Specificity Expressed in the hippocampus and the cerebral cortex.
KEGG Pathway
Nucleocytoplasmic transport (hsa03013 )
Spliceosome (hsa03040 )
Reactome Pathway
mRNA 3'-end processing (R-HSA-72187 )
RNA Polymerase II Transcription Termination (R-HSA-73856 )
Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236 )

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
X-linked intellectual disability DISYJBY3 Definitive Genetic Variation [1]
Intellectual disability DISMBNXP Strong Genetic Variation [2]
Melanoma DIS1RRCY Strong Biomarker [3]
X-linked intellectual disability-short stature-overweight syndrome DISJ2W6X Strong X-linked [4]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
5 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 2 (THOC2). [5]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of THO complex subunit 2 (THOC2). [12]
TAK-243 DM4GKV2 Phase 1 TAK-243 decreases the sumoylation of THO complex subunit 2 (THOC2). [13]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of THO complex subunit 2 (THOC2). [15]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of THO complex subunit 2 (THOC2). [15]
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10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of THO complex subunit 2 (THOC2). [6]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of THO complex subunit 2 (THOC2). [7]
Selenium DM25CGV Approved Selenium decreases the expression of THO complex subunit 2 (THOC2). [8]
Piroxicam DMTK234 Approved Piroxicam increases the expression of THO complex subunit 2 (THOC2). [9]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of THO complex subunit 2 (THOC2). [10]
Genistein DM0JETC Phase 2/3 Genistein decreases the expression of THO complex subunit 2 (THOC2). [11]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of THO complex subunit 2 (THOC2). [8]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of THO complex subunit 2 (THOC2). [14]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of THO complex subunit 2 (THOC2). [16]
methyl p-hydroxybenzoate DMO58UW Investigative methyl p-hydroxybenzoate increases the expression of THO complex subunit 2 (THOC2). [17]
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⏷ Show the Full List of 10 Drug(s)

References

1 Localization of non-specific X-linked mental retardation genes.Am J Med Genet. 1992 Apr 15-May 1;43(1-2):392-401. doi: 10.1002/ajmg.1320430160.
2 Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery.Hum Mutat. 2018 Aug;39(8):1126-1138. doi: 10.1002/humu.23557. Epub 2018 Jun 14.
3 Knockdown THOC2 suppresses the proliferation and invasion of melanoma.Bioengineered. 2019 Dec;10(1):635-645. doi: 10.1080/21655979.2019.1685727.
4 A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia. J Med Genet. 2013 Aug;50(8):543-51. doi: 10.1136/jmedgenet-2013-101542. Epub 2013 Jun 7.
5 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.
6 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.
7 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.
8 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.
9 Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
10 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
11 Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
12 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.
13 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
14 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.
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 Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
17 Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.