Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT69PWBM)

• DOT Name: DNA-directed RNA polymerase III subunit RPC5 (POLR3E)
• Synonyms: RNA polymerase III subunit C5; DNA-directed RNA polymerase III 80 kDa polypeptide
• Gene Name: POLR3E
• Related Disease:
  Agammaglobulinemia
  Chronic granulomatous disease
  Immunodeficiency
  Paroxysmal nocturnal haemoglobinuria
  Renal fibrosis
  Vulvar squamous intraepithelial lesion
  Neoplasm
  Cutaneous squamous cell carcinoma
• UniProt ID: RPC5_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7ASU; 7ASV; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 8ITY; 8IUE; 8IUH
• Pfam ID: PF04801 ; PF19725
• Sequence:
  MANEEDDPVVQEIDVYLAKSLAEKLYLFQYPVRPASMTYDDIPHLSAKIKPKQQKVELEM
  AIDTLNPNYCRSKGEQIALNVDGACADETSTYSSKLMDKQTFCSSQTTSNTSRYAAALYR
  QGELHLTPLHGILQLRPSFSYLDKADAKHREREAANEAGDSSQDEAEDDVKQITVRFSRP
  ESEQARQRRVQSYEFLQKKHAEEPWVHLHYYGLRDSRSEHERQYLLCPGSSGVENTELVK
  SPSEYLMMLMPPSQEEEKDKPVAPSNVLSMAQLRTLPLADQIKILMKNVKVMPFANLMSL
  LGPSIDSVAVLRGIQKVAMLVQGNWVVKSDILYPKDSSSPHSGVPAEVLCRGRDFVMWKF
  TQSRWVVRKEVATVTKLCAEDVKDFLEHMAVVRINKGWEFILPYDGEFIKKHPDVVQRQH
  MLWTGIQAKLEKVYNLVKETMPKKPDAQSGPAGLVCGDQRIQVAKTKAQQNHALLERELQ
  RRKEQLRVPAVPPGVRIKEEPVSEEGEEDEEQEAEEEPMDTSPSGLHSKLANGLPLGRAA
  GTDSFNGHPPQGCASTPVARELKAFVEATFQRQFVLTLSELKRLFNLHLASLPPGHTLFS
  GISDRMLQDTVLAAGCKQILVPFPPQTAASPDEQKVFALWESGDMSDQHRQVLLEIFSKN
  YRVRRNMIQSRLTQECGEDLSKQEVDKVLKDCCVSYGGMWYLKGTVQS
• 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. Assembles with POLR3D/RPC4 forming a subcomplex that binds the Pol III core. Enables recruitment of Pol III at transcription initiation site and drives transcription initiation from both type 2 and type 3 DNA promoters. Required for efficient transcription termination and reinitiation. 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.
• 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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Agammaglobulinemia	DISXMS80	Strong	Biomarker	[1]
Chronic granulomatous disease	DIS9ZR24	Strong	Biomarker	[2]
Immunodeficiency	DIS093I0	Strong	Biomarker	[3]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Biomarker	[4]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[5]
Vulvar squamous intraepithelial lesion	DISULIZR	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Disputed	Biomarker	[6]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[7]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[14]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[21]
AHPN	DM8G6O4	Investigative	AHPN increases the expression of DNA-directed RNA polymerase III subunit RPC5 (POLR3E).	[22]

References

• [1] Induction of human immunoglobulin synthesis and secretion in somatic cell hybrids of mouse myeloma and human B lymphocytes from patients with agammaglobulinemia.J Exp Med. 1978 Oct 1;148(4):974-86. doi: 10.1084/jem.148.4.974.
• [2] Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent.Clin Immunol. 2018 Aug;193:52-59. doi: 10.1016/j.clim.2018.01.010. Epub 2018 Feb 3.
• [3] New - and SIN -retrovectors for safe transduction and specific transgene expression in pancreatic cell lines.BMC Biotechnol. 2019 Jun 17;19(1):35. doi: 10.1186/s12896-019-0531-9.
• [4] A SIN lentiviral vector containing PIGA cDNA allows long-term phenotypic correction of CD34+-derived cells from patients with paroxysmal nocturnal hemoglobinuria.Mol Ther. 2003 Mar;7(3):304-16. doi: 10.1016/s1525-0016(03)00011-x.
• [5] Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study.Evid Based Complement Alternat Med. 2017;2017:6878795. doi: 10.1155/2017/6878795. Epub 2017 Jul 17.
• [6] Sindbis virus replicon particles encoding calreticulin linked to a tumor antigen generate long-term tumor-specific immunity.Cancer Gene Ther. 2006 Sep;13(9):873-85. doi: 10.1038/sj.cgt.7700956. Epub 2006 Apr 28.
• [7] Expression and function of NET-1 in human skin squamous cell carcinoma.Arch Dermatol Res. 2014 May;306(4):385-97. doi: 10.1007/s00403-013-1423-9. Epub 2013 Nov 7.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [11] 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.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [16] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [17] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [19] 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.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. Cancer Res. 2004 Apr 1;64(7):2439-48. doi: 10.1158/0008-5472.can-03-2643.