Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVAW3P1)

• DOT Name: General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3)
• Synonyms: TFIIH subunit XPB; EC 3.6.4.12; Basic transcription factor 2 89 kDa subunit; BTF2 p89; DNA excision repair protein ERCC-3; DNA repair protein complementing XP-B cells; TFIIH basal transcription factor complex 89 kDa subunit; TFIIH 89 kDa subunit; TFIIH p89; Xeroderma pigmentosum group B-complementing protein
• Gene Name: ERCC3
• Related Disease:
  Epithelial ovarian cancer
  Ovarian neoplasm
  Xeroderma pigmentosum group B
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Carcinoma of esophagus
  Cardiovascular disease
  Colorectal carcinoma
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  High blood pressure
  Leukopenia
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Nasal polyp
  Neoplasm of esophagus
  Osteosarcoma
  Premature aging syndrome
  Prostate cancer
  Prostate carcinoma
  Skin cancer
  Skin disease
  Spinal muscular atrophy
  Stomach cancer
  Trichohepatoenteric syndrome
  Trichothiodystrophy 1, photosensitive
  Venous thromboembolism
  Xeroderma pigmentosum group D
  Breast carcinoma
  Head-neck squamous cell carcinoma
  Melanoma
  Neoplasm
  Plasma cell myeloma
  Trichothiodystrophy
  Xeroderma pigmentosum
  Xeroderma pigmentosum-Cockayne syndrome complex
  Cowden disease
  Ovarian cancer
  Cockayne syndrome
  Trichothiodystrophy 2, photosensitive
• UniProt ID: ERCC3_HUMAN
• PDB ID: 4ERN ; 5IVW ; 5IY6 ; 5IY7 ; 5IY8 ; 5IY9 ; 5OF4 ; 6NMI ; 6O9L ; 6O9M ; 6RO4 ; 7AD8 ; 7EGB ; 7EGC ; 7ENA ; 7ENC ; 7LBM ; 7NVR ; 7NVV ; 7NVW ; 7NVX ; 7NVY ; 7NVZ ; 7NW0 ; 8BVW ; 8BYQ ; 8EBS ; 8EBT ; 8EBU ; 8EBV ; 8EBW ; 8EBX ; 8EBY ; 8GXQ ; 8GXS ; 8WAK ; 8WAL ; 8WAN ; 8WAO ; 8WAP ; 8WAQ ; 8WAR ; 8WAS
• EC Number: 3.6.4.12
• Pfam ID: PF16203 ; PF13625 ; PF04851
• Sequence:
  MGKRDRADRDKKKSRKRHYEDEEDDEEDAPGNDPQEAVPSAAGKQVDESGTKVDEYGAKD
  YRLQMPLKDDHTSRPLWVAPDGHIFLEAFSPVYKYAQDFLVAIAEPVCRPTHVHEYKLTA
  YSLYAAVSVGLQTSDITEYLRKLSKTGVPDGIMQFIKLCTVSYGKVKLVLKHNRYFVESC
  HPDVIQHLLQDPVIRECRLRNSEGEATELITETFTSKSAISKTAESSGGPSTSRVTDPQG
  KSDIPMDLFDFYEQMDKDEEEEEETQTVSFEVKQEMIEELQKRCIHLEYPLLAEYDFRND
  SVNPDINIDLKPTAVLRPYQEKSLRKMFGNGRARSGVIVLPCGAGKSLVGVTAACTVRKR
  CLVLGNSAVSVEQWKAQFKMWSTIDDSQICRFTSDAKDKPIGCSVAISTYSMLGHTTKRS
  WEAERVMEWLKTQEWGLMILDEVHTIPAKMFRRVLTIVQAHCKLGLTATLVREDDKIVDL
  NFLIGPKLYEANWMELQNNGYIAKVQCAEVWCPMSPEFYREYVAIKTKKRILLYTMNPNK
  FRACQFLIKFHERRNDKIIVFADNVFALKEYAIRLNKPYIYGPTSQGERMQILQNFKHNP
  KINTIFISKVGDTSFDLPEANVLIQISSHGGSRRQEAQRLGRVLRAKKGMVAEEYNAFFY
  SLVSQDTQEMAYSTKRQRFLVDQGYSFKVITKLAGMEEEDLAFSTKEEQQQLLQKVLAAT
  DLDAEEEVVAGEFGSRSSQASRRFGTMSSMSGADDTVYMEYHSSRSKAPSKHVHPLFKRF
  RK
• Function: ATP-dependent 3'-5' DNA helicase, 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. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening. 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. The ATP-dependent helicase activity of XPB/ERCC3 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)
• 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

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[1]
Xeroderma pigmentosum group B	DIS1EFEV	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
High blood pressure	DISY2OHH	Strong	Altered Expression	[7]
Leukopenia	DISJMBMM	Strong	Posttranslational Modification	[11]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[12]
Nasal polyp	DISLP3XE	Strong	Genetic Variation	[13]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[4]
Premature aging syndrome	DIS51AGT	Strong	Genetic Variation	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[14]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[14]
Skin cancer	DISTM18U	Strong	Biomarker	[15]
Skin disease	DISDW8R6	Strong	Altered Expression	[16]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[17]
Stomach cancer	DISKIJSX	Strong	Biomarker	[9]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[18]
Trichothiodystrophy 1, photosensitive	DISK51NL	Strong	Autosomal recessive	[19]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[20]
Xeroderma pigmentosum group D	DISFFE93	Strong	Genetic Variation	[21]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[5]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[22]
Melanoma	DIS1RRCY	moderate	Altered Expression	[23]
Neoplasm	DISZKGEW	moderate	Altered Expression	[24]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[25]
Trichothiodystrophy	DISOMQD2	Supportive	Autosomal recessive	[26]
Xeroderma pigmentosum	DISQ9H19	Supportive	Autosomal recessive	[27]
Xeroderma pigmentosum-Cockayne syndrome complex	DISJ0QRY	Supportive	Autosomal recessive	[27]
Cowden disease	DISMYKCE	Disputed	Genetic Variation	[28]
Ovarian cancer	DISZJHAP	Disputed	Biomarker	[1]
Cockayne syndrome	DISW6GL2	Limited	Biomarker	[29]
Trichothiodystrophy 2, photosensitive	DISW8OID	Limited	Autosomal recessive	[30]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3) increases the response to substance of Bortezomib.	[41]

12 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 and DNA repair factor IIH helicase subunit XPB (ERCC3).	[31]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[32]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[33]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[34]
Menthol	DMG2KW7	Approved	Menthol increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[35]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[36]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[37]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[37]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of General transcription and DNA repair factor IIH helicase subunit XPB (ERCC3).	[40]

References

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• [31] 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.
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• [35] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
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• [39] Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes. Biochem Pharmacol. 2017 Aug 1;137:113-124.
• [40] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [41] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.