Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK72L9I)

• DOT Name: General transcription factor IIH subunit 2 (GTF2H2)
• Synonyms: Basic transcription factor 2 44 kDa subunit; BTF2 p44; General transcription factor IIH polypeptide 2; TFIIH basal transcription factor complex p44 subunit
• Gene Name: GTF2H2
• Related Disease:
  Lung neoplasm
  Xeroderma pigmentosum group B
  Xeroderma pigmentosum group G
  Advanced cancer
  Benign prostatic hyperplasia
  Cockayne syndrome type 1
  Ductal breast carcinoma in situ
  Melanoma
  Neoplasm of testis
  Rift valley fever
  Seminoma
  Skin disease
  Spinal muscular atrophy, type 1
  Xeroderma pigmentosum group A
  Xeroderma pigmentosum group D
  Xeroderma pigmentosum-Cockayne syndrome complex
  Head-neck squamous cell carcinoma
  Neoplasm
  Skin cancer
  Cowden disease
  Breast cancer
  Breast carcinoma
  Cockayne syndrome
  Prostate cancer
  Prostate carcinoma
  Trichothiodystrophy
• UniProt ID: TF2H2_HUMAN
• PDB ID: 1Z60 ; 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: PF07975 ; PF04056
• Sequence:
  MDEEPERTKRWEGGYERTWEILKEDESGSLKATIEDILFKAKRKRVFEHHGQVRLGMMRH
  LYVVVDGSRTMEDQDLKPNRLTCTLKLLEYFVEEYFDQNPISQIGIIVTKSKRAEKLTEL
  SGNPRKHITSLKKAVDMTCHGEPSLYNSLSIAMQTLKHMPGHTSREVLIIFSSLTTCDPS
  NIYDLIKTLKAAKIRVSVIGLSAEVRVCTVLARETGGTYHVILDESHYKELLTHHVSPPP
  ASSSSECSLIRMGFPQHTIASLSDQDAKPSFSMAHLDGNTEPGLTLGGYFCPQCRAKYCE
  LPVECKICGLTLVSAPHLARSYHHLFPLDAFQEIPLEEYNGERFCYGCQGELKDQHVYVC
  AVCQNVFCVDCDVFVHDSLHCCPGCIHKIPAPSGV
• 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. The N-terminus of GTF2H2 interacts with and regulates XPD whereas an intact C-terminus is required for a successful escape of RNAP II form the promoter.
• Tissue Specificity: Widely expressed, with higher expression in skeletal muscle.
• 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

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung neoplasm	DISVARNB	Definitive	Biomarker	[1]
Xeroderma pigmentosum group B	DIS1EFEV	Definitive	Biomarker	[2]
Xeroderma pigmentosum group G	DIS4PV33	Definitive	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Genetic Variation	[5]
Cockayne syndrome type 1	DIS9JFVY	Strong	Biomarker	[6]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[7]
Melanoma	DIS1RRCY	Strong	Altered Expression	[8]
Neoplasm of testis	DISK4XHT	Strong	Altered Expression	[9]
Rift valley fever	DISG6CM2	Strong	Altered Expression	[10]
Seminoma	DIS3J8LJ	Strong	Altered Expression	[9]
Skin disease	DISDW8R6	Strong	Altered Expression	[11]
Spinal muscular atrophy, type 1	DISYCWUG	Strong	Altered Expression	[12]
Xeroderma pigmentosum group A	DIS38HWC	Strong	Genetic Variation	[13]
Xeroderma pigmentosum group D	DISFFE93	Strong	Biomarker	[14]
Xeroderma pigmentosum-Cockayne syndrome complex	DISJ0QRY	Strong	Genetic Variation	[15]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[16]
Neoplasm	DISZKGEW	moderate	Altered Expression	[16]
Skin cancer	DISTM18U	moderate	Altered Expression	[17]
Cowden disease	DISMYKCE	Disputed	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[18]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[18]
Cockayne syndrome	DISW6GL2	Limited	Biomarker	[19]
Prostate cancer	DISF190Y	Limited	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[1]
Trichothiodystrophy	DISOMQD2	Limited	Altered Expression	[20]

10 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 2 (GTF2H2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[22]
Selenium	DM25CGV	Approved	Selenium decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[25]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of General transcription factor IIH subunit 2 (GTF2H2).	[29]

References

• [1] Protein arginine methyltransferase 5 regulates multiple signaling pathways to promote lung cancer cell proliferation.BMC Cancer. 2016 Aug 2;16:567. doi: 10.1186/s12885-016-2632-3.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Roles of the androgen receptor cofactor p44 in the growth of prostate epithelial cells.J Mol Endocrinol. 2006 Oct;37(2):283-300. doi: 10.1677/jme.1.02062.
• [6] 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.
• [7] Androgen receptor coactivator p44/Mep50 in breast cancer growth and invasion.J Cell Mol Med. 2010 Dec;14(12):2780-9. doi: 10.1111/j.1582-4934.2009.00936.x.
• [8] 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.
• [9] The expression and function of androgen receptor coactivator p44 and protein arginine methyltransferase 5 in the developing testis and testicular tumors.J Urol. 2007 May;177(5):1918-22. doi: 10.1016/j.juro.2007.01.017.
• [10] 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.
• [11] Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein.Hum Mutat. 1998;12(2):103-13. doi: 10.1002/(SICI)1098-1004(1998)12:2<103::AID-HUMU5>3.0.CO;2-6.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.Eur J Hum Genet. 2017 Apr;25(4):432-438. doi: 10.1038/ejhg.2016.203. Epub 2017 Feb 1.
• [19] 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.
• [20] 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.
• [21] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [22] 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.
• [23] 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.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Benzo[a]pyrene increases the Nrf2 content by downregulating the Keap1 message. Toxicol Sci. 2010 Aug;116(2):549-61.
• [26] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [27] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.