Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZCSF6A)

• DOT Name: DNA-directed RNA polymerase III subunit RPC10 (POLR3K)
• Synonyms: RNA polymerase III subunit C10; DNA-directed RNA polymerase III subunit K; RNA polymerase III 12.5 kDa subunit; RPC12.5; RNA polymerase III subunit C11; HsC11p; RPC11; hRPC11
• Gene Name: POLR3K
• Related Disease:
  Chikungunya virus infection
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Leukodystrophy, hypomyelinating, 21
• UniProt ID: RPC10_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 8ITY; 8IUE; 8IUH
• Pfam ID: PF02150 ; PF01096
• Sequence:
  MLLFCPGCGNGLIVEEGQRCHRFACNTCPYVHNITRKVTNRKYPKLKEVDDVLGGAAAWE
  NVDSTAESCPKCEHPRAYFMQLQTRSADEPMTTFYKCCNAQCGHRWRD
• Function: Core component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. Can mediate Pol I proofreading of the nascent RNA transcript. Anchors into the Pol III active site to constantly monitor transcription fidelity, cleaves mis-incorporated 5'-ribonucleotides and restarts the transcription process. Once Pol III reaches the poly(dT) termination signal, can induce Pol III clamp opening and transcription termination. Pol III plays an important 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.
• 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
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[1]
Gastric cancer	DISXGOUK	Strong	Biomarker	[2]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[2]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[2]
Leukodystrophy, hypomyelinating, 21	DIS2KO3L	Limited	Unknown	[3]

12 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 RPC10 (POLR3K).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA-directed RNA polymerase III subunit RPC10 (POLR3K).	[15]

References

• [1] Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway.J Virol. 2018 Feb 26;92(6):e01913-17. doi: 10.1128/JVI.01913-17. Print 2018 Mar 15.
• [2] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [3] Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation. Neurol Genet. 2018 Dec 3;4(6):e289. doi: 10.1212/NXG.0000000000000289. eCollection 2018 Dec.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [10] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [11] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.