Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU3TGQ9)

• DOT Name: DNA-directed RNA polymerase III subunit RPC7 (POLR3G)
• Synonyms: RNA polymerase III subunit C7; DNA-directed RNA polymerase III subunit G; RNA polymerase III 32 kDa apha subunit; RPC32-alpha; RNA polymerase III 32 kDa subunit; RPC32
• Gene Name: POLR3G
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Neoplasm
  Advanced cancer
  Chronic hepatitis B virus infection
• UniProt ID: RPC7_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 8ITY; 8IUE; 8IUH
• Pfam ID: PF11705
• Sequence:
  MAGNKGRGRAAYTFNIEAVGFSKGEKLPDVVLKPPPLFPDTDYKPVPLKTGEGEEYMLAL
  KQELRETMKRMPYFIETPEERQDIERYSKRYMKVYKEEWIPDWRRLPREMMPRNKCKKAG
  PKPKKAKDAGKGTPLTNTEDVLKKMEELEKRGDGEKSDEENEEKEGSKEKSKEGDDDDDD
  DAAEQEEYDEEEQEEENDYINSYFEDGDDFGADSDDNMDEATY
• Function: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. Acts as a long tether that bridges POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer and the mobile stalk of Pol III, coordinating the dynamics of Pol III stalk and clamp modules during the transition from apo to elongation state. Pol III exists as two alternative complexes defined by the mutually exclusive incorporation of subunit POLR3G/RPC7alpha or POLR3GL/RPC7beta. POLR3G/RPC7alpha modulates Pol III transcriptome by specifically enhancing the transcription of snaR-A non-coding RNAs. At resting state, occupies the active site of apo Pol III and keeps Pol III in an autoinhibitory mode, preventing non-specific transcription. Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as a nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs), induce type I interferon and NF-kappa-B through the RIG-I pathway.
• Tissue Specificity: Barely detectable in differentiated tissues. Expressed in embryonic stem cells and in other dividing cells, such as some tumor cell lines.
• KEGG Pathway:
  R. polymerase (hsa03020)
  Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  RNA Polymerase III Chain Elongation (R-HSA-73780)
  RNA Polymerase III Transcription Termination (R-HSA-73980)
  RNA Polymerase III Abortive And Retractive Initiation (R-HSA-749476)
  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 Transcription Initiation From Type 3 Promoter (R-HSA-76071)
  Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	moderate	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	DNA-directed RNA polymerase III subunit RPC7 (POLR3G) increases the response to substance of Irinotecan.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[13]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[14]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[14]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA-directed RNA polymerase III subunit RPC7 (POLR3G).	[23]

References

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• [2] Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies.Gut. 2017 Apr;66(4):581-587. doi: 10.1136/gutjnl-2015-310612. Epub 2015 Dec 23.
• [3] Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression.J Clin Invest. 2016 Oct 3;126(10):4045-4060. doi: 10.1172/JCI86042. Epub 2016 Sep 19.
• [4] Genetic variation in FCER1A predicts peginterferon alfa-2a-induced hepatitis B surface antigen clearance in East Asian patients with chronic hepatitis B.J Viral Hepat. 2019 Sep;26(9):1040-1049. doi: 10.1111/jvh.13107. Epub 2019 Jul 23.
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• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] 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.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [20] 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.
• [21] Bisphenol A Analogues Suppress Spheroid Attachment on Human Endometrial Epithelial Cells through Modulation of Steroid Hormone Receptors Signaling Pathway. Cells. 2021 Oct 26;10(11):2882. doi: 10.3390/cells10112882.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.