Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQC6DMG)

• DOT Name: Transcription factor IIIB 90 kDa subunit (BRF1)
• Synonyms: TFIIIB90; hTFIIIB90; B-related factor 1; BRF-1; hBRF; TAF3B2; TATA box-binding protein-associated factor, RNA polymerase III, subunit 2
• Gene Name: BRF1
• Related Disease:
  Cerebellar-facial-dental syndrome
  Congenital thrombotic thrombocytopenic purpura
  Thrombotic thrombocytopenic purpura
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Fibroma
  Hepatocellular carcinoma
  Intellectual disability
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Neoplasm
  Colorectal adenoma
• UniProt ID: TF3B_HUMAN
• Pfam ID: PF07741 ; PF08271 ; PF00382
• Sequence:
  MTGRVCRGCGGTDIELDAARGDAVCTACGSVLEDNIIVSEVQFVESSGGGSSAVGQFVSL
  DGAGKTPTLGGGFHVNLGKESRAQTLQNGRRHIHHLGNQLQLNQHCLDTAFNFFKMAVSR
  HLTRGRKMAHVIAACLYLVCRTEGTPHMLLDLSDLLQVNVYVLGKTFLLLARELCINAPA
  IDPCLYIPRFAHLLEFGEKNHEVSMTALRLLQRMKRDWMHTGRRPSGLCGAALLVAARMH
  DFRRTVKEVISVVKVCESTLRKRLTEFEDTPTSQLTIDEFMKIDLEEECDPPSYTAGQRK
  LRMKQLEQVLSKKLEEVEGEISSYQDAIEIELENSRPKAKGGLASLAKDGSTEDTASSLC
  GEEDTEDEELEAAASHLNKDLYRELLGGAPGSSEAAGSPEWGGRPPALGSLLDPLPTAAS
  LGISDSIRECISSQSSDPKDASGDGELDLSGIDDLEIDRYILNESEARVKAELWMRENAE
  YLREQREKEARIAKEKELGIYKEHKPKKSCKRREPIQASTAREAIEKMLEQKKISSKINY
  SVLRGLSSAGGGSPHREDAQPEHSASARKLSRRRTPASRSGADPVTSVGKRLRPLVSTQP
  AKKVATGEALLPSSPTLGAEPARPQAVLVESGPVSYHADEEADEEEPDEEDGEPCVSALQ
  MMGSNDYGCDGDEDDGY
• Function: General activator of RNA polymerase which utilizes different TFIIIB complexes at structurally distinct promoters. The isoform 1 is involved in the transcription of tRNA, adenovirus VA1, 7SL and 5S RNA. Isoform 2 is required for transcription of the U6 promoter.
• Reactome Pathway:
  RNA Polymerase III Transcription Initiation From Type 1 Promoter (R-HSA-76061)
  RNA Polymerase III Transcription Initiation From Type 2 Promoter (R-HSA-76066)
  RNA Polymerase III Abortive And Retractive Initiation (R-HSA-749476)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebellar-facial-dental syndrome	DISYVR8V	Definitive	Autosomal recessive	[1]
Congenital thrombotic thrombocytopenic purpura	DISC8GS9	Definitive	Biomarker	[2]
Thrombotic thrombocytopenic purpura	DIS3LDOU	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Fibroma	DISH5078	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Intellectual disability	DISMBNXP	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[4]
Neoplasm	DISZKGEW	Disputed	Biomarker	[8]
Colorectal adenoma	DISTSVHM	Limited	Autosomal dominant	[9]

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 Transcription factor IIIB 90 kDa subunit (BRF1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcription factor IIIB 90 kDa subunit (BRF1).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Transcription factor IIIB 90 kDa subunit (BRF1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Transcription factor IIIB 90 kDa subunit (BRF1).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transcription factor IIIB 90 kDa subunit (BRF1).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Transcription factor IIIB 90 kDa subunit (BRF1).	[11]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Transcription factor IIIB 90 kDa subunit (BRF1).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Transcription factor IIIB 90 kDa subunit (BRF1).	[13]
ELLAGIC ACID	DMX8BS5	Investigative	ELLAGIC ACID decreases the expression of Transcription factor IIIB 90 kDa subunit (BRF1).	[13]

References

• [1] BRF1 mutations alter RNA polymerase III-dependent transcription and cause neurodevelopmental anomalies. Genome Res. 2015 Feb;25(2):155-66. doi: 10.1101/gr.176925.114. Epub 2015 Jan 5.
• [2] IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3.Immunol Cell Biol. 2019 Jan;97(1):54-71. doi: 10.1111/imcb.12200. Epub 2018 Oct 19.
• [3] Alcohol Intake and Abnormal Expression of Brf1 in Breast Cancer.Oxid Med Cell Longev. 2019 Oct 31;2019:4818106. doi: 10.1155/2019/4818106. eCollection 2019.
• [4] Association Between Germline Mutations in BRF1, a Subunit of the RNA Polymerase III Transcription Complex, and Hereditary Colorectal Cancer.Gastroenterology. 2018 Jan;154(1):181-194.e20. doi: 10.1053/j.gastro.2017.09.005. Epub 2017 Sep 12.
• [5] Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation.J Biol Chem. 2008 Jul 11;283(28):19184-91. doi: 10.1074/jbc.M802872200. Epub 2008 May 1.
• [6] The RNA polymerase III repressor MAF1 is regulated by ubiquitin-dependent proteasome degradation and modulates cancer drug resistance and apoptosis. J Biol Chem. 2019 Dec 13;294(50):19255-19268. doi: 10.1074/jbc.RA119.008849. Epub 2019 Oct 23.
• [7] BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration.Oncogene. 2020 Feb;39(8):1797-1806. doi: 10.1038/s41388-019-1106-x. Epub 2019 Nov 18.
• [8] Cellular senescence bypass screen identifies new putative tumor suppressor genes.Oncogene. 2008 Mar 27;27(14):1961-70. doi: 10.1038/sj.onc.1210846. Epub 2007 Oct 29.
• [9] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [10] 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.
• [11] The significance of Runx2 mediating alcohol-induced Brf1 expression and RNA Pol III gene transcription. Chem Biol Interact. 2020 May 25;323:109057. doi: 10.1016/j.cbi.2020.109057. Epub 2020 Mar 18.
• [12] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [13] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [14] 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.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.