Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT87W5QJ)

• DOT Name: General transcription factor IIH subunit 3 (GTF2H3)
• Synonyms: Basic transcription factor 2 34 kDa subunit; BTF2 p34; General transcription factor IIH polypeptide 3; TFIIH basal transcription factor complex p34 subunit
• Gene Name: GTF2H3
• Related Disease:
  Xeroderma pigmentosum group B
  Xeroderma pigmentosum group G
  Advanced cancer
  Ataxia-telangiectasia
  Cockayne syndrome type 1
  Familial adenomatous polyposis
  Melanoma
  Prostate cancer
  Prostate carcinoma
  Rift valley fever
  Skin disease
  Spinal muscular atrophy
  Spinal muscular atrophy, type 1
  Xeroderma pigmentosum group A
  Xeroderma pigmentosum group D
  Xeroderma pigmentosum-Cockayne syndrome complex
  Head-neck squamous cell carcinoma
  Skin cancer
  Cowden disease
  Cockayne syndrome
  Trichothiodystrophy
• UniProt ID: TF2H3_HUMAN
• PDB ID: 5IVW ; 5IY6 ; 5IY7 ; 5IY8 ; 5IY9 ; 5O85 ; 5OF4 ; 6NMI ; 6O9L ; 6O9M ; 6RO4 ; 7AD8 ; 7EGB ; 7EGC ; 7ENA ; 7ENC ; 7LBM ; 7NVR ; 7NVW ; 7NVX ; 7NVY ; 7NVZ ; 7NW0 ; 8BVW ; 8BYQ ; 8EBS ; 8EBT ; 8EBU ; 8EBV ; 8EBW ; 8EBX ; 8EBY ; 8GXQ ; 8GXS ; 8WAK ; 8WAL ; 8WAN ; 8WAO ; 8WAP ; 8WAQ ; 8WAR ; 8WAS
• Pfam ID: PF03850
• Sequence:
  MVSDEDELNLLVIVVDANPIWWGKQALKESQFTLSKCIDAVMVLGNSHLFMNRSNKLAVI
  ASHIQESRFLYPGKNGRLGDFFGDPGNPPEFNPSGSKDGKYELLTSANEVIVEEIKDLMT
  KSDIKGQHTETLLAGSLAKALCYIHRMNKEVKDNQEMKSRILVIKAAEDSALQYMNFMNV
  IFAAQKQNILIDACVLDSDSGLLQQACDITGGLYLKVPQMPSLLQYLLWVFLPDQDQRSQ
  LILPPPVHVDYRAACFCHRNLIEIGYVCSVCLSIFCNFSPICTTCETAFKISLPPVLKAK
  KKKLKVSA
• Function: Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.
• KEGG Pathway:
  Basal transcription factors (hsa03022)
  Nucleotide excision repair (hsa03420)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  RNA Pol II CTD phosphorylation and interaction with CE during HIV infection (R-HSA-167160)
  HIV Transcription Initiation (R-HSA-167161)
  RNA Polymerase II HIV Promoter Escape (R-HSA-167162)
  Transcription of the HIV genome (R-HSA-167172)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  NoRC negatively regulates rRNA expression (R-HSA-427413)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Dual Incision in GG-NER (R-HSA-5696400)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  mRNA Capping (R-HSA-72086)
  RNA Polymerase I Transcription Initiation (R-HSA-73762)
  RNA Polymerase I Promoter Escape (R-HSA-73772)
  RNA Polymerase II Promoter Escape (R-HSA-73776)
  RNA Polymerase II Transcription Pre-Initiation And Promoter Opening (R-HSA-73779)
  RNA Polymerase I Transcription Termination (R-HSA-73863)
  RNA Polymerase II Transcription Initiation (R-HSA-75953)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  RNA Polymerase II Transcription Initiation And Promoter Clearance (R-HSA-76042)
  RNA Pol II CTD phosphorylation and interaction with CE (R-HSA-77075)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Xeroderma pigmentosum group B	DIS1EFEV	Definitive	Biomarker	[1]
Xeroderma pigmentosum group G	DIS4PV33	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[4]
Cockayne syndrome type 1	DIS9JFVY	Strong	Biomarker	[5]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[6]
Melanoma	DIS1RRCY	Strong	Altered Expression	[7]
Prostate cancer	DISF190Y	Strong	Altered Expression	[8]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Rift valley fever	DISG6CM2	Strong	Altered Expression	[9]
Skin disease	DISDW8R6	Strong	Genetic Variation	[10]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[11]
Spinal muscular atrophy, type 1	DISYCWUG	Strong	Altered Expression	[11]
Xeroderma pigmentosum group A	DIS38HWC	Strong	Genetic Variation	[12]
Xeroderma pigmentosum group D	DISFFE93	Strong	Biomarker	[13]
Xeroderma pigmentosum-Cockayne syndrome complex	DISJ0QRY	Strong	Genetic Variation	[14]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[15]
Skin cancer	DISTM18U	moderate	Altered Expression	[16]
Cowden disease	DISMYKCE	Disputed	Genetic Variation	[2]
Cockayne syndrome	DISW6GL2	Limited	Biomarker	[17]
Trichothiodystrophy	DISOMQD2	Limited	Altered Expression	[18]

1 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 General transcription factor IIH subunit 3 (GTF2H3).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[26]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of General transcription factor IIH subunit 3 (GTF2H3).	[27]

References

• [1] Analysis of the conserved NER helicases (XPB and XPD) and UV-induced DNA damage in Hydra.Biochim Biophys Acta Gen Subj. 2018 Sep;1862(9):2031-2042. doi: 10.1016/j.bbagen.2018.06.017. Epub 2018 Jun 28.
• [2] Regulation of Transcription Elongation by the XPG-TFIIH Complex Is Implicated in Cockayne Syndrome.Mol Cell Biol. 2015 Sep;35(18):3178-88. doi: 10.1128/MCB.01401-14. Epub 2015 Jul 6.
• [3] Rare diseases provide rare insights into DNA repair pathways, TFIIH, aging and cancer center.DNA Repair (Amst). 2005 Feb 3;4(2):293-302. doi: 10.1016/j.dnarep.2004.09.010.
• [4] Ionizing radiation-induced phosphorylation of RPA p34 is deficient in ataxia telangiectasia and reduced in aged normal fibroblasts.Radiother Oncol. 1996 Apr;39(1):43-52. doi: 10.1016/0167-8140(96)01712-4.
• [5] Cockayne syndrome protein A is a transcription factor of RNA polymerase I and stimulates ribosomal biogenesis and growth.Cell Cycle. 2014;13(13):2029-37. doi: 10.4161/cc.29018. Epub 2014 Apr 29.
• [6] Phosphorylation of the tumor suppressor adenomatous polyposis coli (APC) by the cyclin-dependent kinase p34.J Biol Chem. 1997 Aug 29;272(35):21681-4. doi: 10.1074/jbc.272.35.21681.
• [7] Lineage-specific control of TFIIH by MITF determines transcriptional homeostasis and DNA repair.Oncogene. 2019 May;38(19):3616-3635. doi: 10.1038/s41388-018-0661-x. Epub 2019 Jan 16.
• [8] From androgen receptor to the general transcription factor TFIIH. Identification of cdk activating kinase (CAK) as an androgen receptor NH(2)-terminal associated coactivator.J Biol Chem. 2000 Mar 31;275(13):9308-13. doi: 10.1074/jbc.275.13.9308.
• [9] Virulence factor NSs of rift valley fever virus recruits the F-box protein FBXO3 to degrade subunit p62 of general transcription factor TFIIH.J Virol. 2014 Mar;88(6):3464-73. doi: 10.1128/JVI.02914-13. Epub 2014 Jan 8.
• [10] Clathrin Adaptor Complex-interacting Protein Irc6 Functions through the Conserved C-Terminal Domain.Sci Rep. 2019 Mar 14;9(1):4436. doi: 10.1038/s41598-019-40852-8.
• [11] The gene encoding p44, a subunit of the transcription factor TFIIH, is involved in large-scale deletions associated with Werdnig-Hoffmann disease.Am J Hum Genet. 1997 Jan;60(1):72-9.
• [12] Mutational analysis of a function of xeroderma pigmentosum group A (XPA) protein in strand-specific DNA repair.Nucleic Acids Res. 1998 Oct 15;26(20):4662-8. doi: 10.1093/nar/26.20.4662.
• [13] MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation.Mol Cell. 2010 Aug 27;39(4):632-40. doi: 10.1016/j.molcel.2010.07.029.
• [14] Suppression of UV-induced apoptosis by the human DNA repair protein XPG.Cell Death Differ. 2006 Mar;13(3):478-88. doi: 10.1038/sj.cdd.4401764.
• [15] PWP1 Mediates Nutrient-Dependent Growth Control through Nucleolar Regulation of Ribosomal Gene Expression.Dev Cell. 2017 Oct 23;43(2):240-252.e5. doi: 10.1016/j.devcel.2017.09.022.
• [16] Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy.Hum Mutat. 2008 Oct;29(10):1194-208. doi: 10.1002/humu.20768.
• [17] Transcription preinitiation complex structure and dynamics provide insight into genetic diseases.Nat Struct Mol Biol. 2019 Jun;26(6):397-406. doi: 10.1038/s41594-019-0220-3. Epub 2019 May 20.
• [18] Small molecule-based targeting of TTD-A dimerization to control TFIIH transcriptional activity represents a potential strategy for anticancer therapy.J Biol Chem. 2018 Sep 28;293(39):14974-14988. doi: 10.1074/jbc.RA118.003444. Epub 2018 Aug 1.
• [19] 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.
• [20] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [21] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [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] 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.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.