Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8TEBYZ)

• DOT Name: THO complex subunit 6 homolog (THOC6)
• Synonyms: Functional spliceosome-associated protein 35; fSAP35; WD repeat-containing protein 58
• Gene Name: THOC6
• Related Disease:
  THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome
  Intellectual disability
• UniProt ID: THOC6_HUMAN
• PDB ID: 7APK; 7ZNK; 7ZNL
• Pfam ID: PF00400
• Sequence:
  MERAVPLAVPLGQTEVFQALQRLHMTIFSQSVSPCGKFLAAGNNYGQIAIFSLSSALSSE
  AKEESKKPVVTFQAHDGPVYSMVSTDRHLLSAGDGEVKAWLWAEMLKKGCKELWRRQPPY
  RTSLEVPEINALLLVPKENSLILAGGDCQLHTMDLETGTFTRVLRGHTDYIHCLALRERS
  PEVLSGGEDGAVRLWDLRTAKEVQTIEVYKHEECSRPHNGRWIGCLATDSDWMVCGGGPA
  LTLWHLRSSTPTTIFPIRAPQKHVTFYQDLILSAGQGRCVNQWQLSGELKAQVPGSSPGL
  LSLSLNQQPAAPECKVLTAAGNSCRVDVFTNLGYRAFSLSF
• 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. Plays a role in apoptosis negative control involved in brain development.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome	DISPBI96	Definitive	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of THO complex subunit 6 homolog (THOC6).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of THO complex subunit 6 homolog (THOC6).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of THO complex subunit 6 homolog (THOC6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of THO complex subunit 6 homolog (THOC6).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of THO complex subunit 6 homolog (THOC6).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of THO complex subunit 6 homolog (THOC6).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of THO complex subunit 6 homolog (THOC6).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of THO complex subunit 6 homolog (THOC6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of THO complex subunit 6 homolog (THOC6).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of THO complex subunit 6 homolog (THOC6).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of THO complex subunit 6 homolog (THOC6).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of THO complex subunit 6 homolog (THOC6).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.Eur J Med Genet. 2020 Mar;63(3):103742. doi: 10.1016/j.ejmg.2019.103742. Epub 2019 Aug 14.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [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] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] 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.
• [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] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.